GPR40

In September last year, the South Korean biopharmaceutical company GPCR Therapeutics published a research paper in "Cell Communication and Signaling" about the direct interaction between two different GPCRs (CXCR4 and LPA1). Through various in vitro experiments, the company discovered that the efficacy of LPA1 inhibitors could be enhanced to its maximum potential by inhibiting CXCR4, thereby providing scientific evidence that the combination of CXCR4-LPA1 inhibitors might be a necessary condition for comprehensive antifibrotic activity. Based on this discovery, GPCR Therapeutics filed a provisional patent application for a combined therapeutic method involving CXCR4-LPA1 inhibitors. GPCR Therapeutics will collaborate with Bridge Biotherapeutics to jointly develop and commercialize this combined therapy. Bridge Biotherapeutics is conducting a phase 2a multinational clinical trial for the autonomic sympatho-inhibitor BBT-877, intended for the treatment of idiopathic pulmonary fibrosis (IPF), and is accelerating the development of its proprietary IPF product pipeline. About Idiopathic Pulmonary FibrosisIdiopathic Pulmonary Fibrosis (IPF) is a progressive chronic lung disease that leads to scarring (fibrosis) of the lungs, resulting in stiffening and loss of elasticity of the lung tissues, making breathing increasingly difficult. The efficiency of oxygen transfer in the lungs decreases, thus the process of oxygen passing from the alveoli to the blood during inhalation is compromised in IPF patients. The lung damage caused by IPF is irreversible, and currently, there are no treatment methods available that can stop or reverse the formation of scarring. The prognosis of Idiopathic Pulmonary Fibrosis is generally poor and the progression of the disease is difficult to predict. For some patients, the disease may progress slowly, whereas for others, it may advance more rapidly. On average, the life expectancy of patients is relatively short. Even in the United States, which has some of the world's leading medical conditions, there are approximately 495 cases per 100,000 people, with a median survival estimated at 2-5 years post-diagnosis. According to statistics from the Synapse database, there are a total of 341 R&D pipelines globally in the direction of idiopathic pulmonary fibrosis, with 4 approved drugs on the market, 6 projects in phase III clinical trials, 40 projects in phase II clinical trials, and 45 projects in phase I clinical trials. GPCR-class targets that are popular research targets for this clinical indication include autotaxin, LPAR1, αvβ6, etc. BMS-986278 is a lysophosphatidic acid receptor 1 (LPAR1) antagonist developed originally by BMS Company. Extensive research indicates that idiopathic pulmonary fibrosis (IPF) can be mediated by lysophosphatidic acid (LPA), which acts through several of the six known lysophosphatidic acid receptor-mediated downstream signaling pathways. The first generation LPAR1 antagonist developed by BMS Company, represented by BMS-986020, exhibited hepatobiliary toxicity and increased plasma bile acids in a phase II clinical trial. Subsequently, BMS Company conducted preclinical studies on the mechanism of hepatic toxicity with BMS-986020 and two structurally different LPA1 antagonists (BMS-986234 and BMS-986278), further confirming that the second-generation LPA1 antagonist BMS-986278 did not show hepatobiliary toxicity in preclinical and clinical safety studies. BMS-986278 is currently in phase II clinical development for the treatment of IPF and progressive fibrotic interstitial lung diseases. In addition to BMS, companies including Sanofi, UBE, Novo Nordisk, and DJS Antibodies have also been involved in the development of drugs targeting LPAR1 for the treatment of idiopathic pulmonary fibrosis. VP01 (C-21) is an AT2R agonist developed by Vicore Pharma. The company recently published research data demonstrating that C21 can reduce the content of TGFβ1 and collagen in human IPF lung slices. In a phase 2a clinical trial, C21 showed good safety and efficacy in newly treated IPF patients, maintaining stable forced vital capacity over a 36-week treatment period. Apart from Vicore Pharma, companies including MorphoSys and Emeriti Bio are also strategizing on the development of therapeutics targeting the AT2R for the treatment of idiopathic pulmonary fibrosis. In 2017, a team from Genentech published a research paper in the journal Thorax, discussing CXCL14 as a potential biomarker for Hedgehog signaling in idiopathic pulmonary fibrosis. Compared to the control group, there is a significant increase in the expression of Hedgehog-associated genes in the lung tissue of patients with Idiopathic Pulmonary Fibrosis (IPF). The most upregulated gene in IPF lung biopsy tissues and fibroblasts subjected to SHh stimulation in vitro was CXCL14, a gene that encodes a soluble secreted chemokine whose expression is inhibited in vitro by vismodegib. Overexpression of SHh in the lungs of mice induces the expression of CXCL14. Circulating levels of CXCL14 protein in the plasma of IPF patients are significantly higher than those in the control group. In cancer patients, circulating levels of CXCL14 decreased significantly after treatment with vismodegib. Therefore, the IL-13 inhibitor Lebrikizumab, originally developed by Genentech, is considered to have potential for the treatment of IPF. Treprostinil is a prostacyclin receptor agonist originally developed by United Therapeutics for the treatment of pulmonary arterial hypertension to alleviate exercise-related symptoms. Treprostinil is a stable, synthetic analog of prostacyclin that promotes vasodilation of the pulmonary and systemic arterial beds and inhibits platelet aggregation. It helps reduce symptoms in patients with Pulmonary Arterial Hypertension (PAH) and patients with pulmonary hypertension associated with interstitial lung disease. The FDA approved Treprostinil for the treatment of PAH in 2002. The first drug approved for the treatment of PAH was epoprostenol, an artificially synthesized prostacyclin, which significantly improves the quality of life for patients. However, the use of epoprostenol has been limited due to its short half-life (3-5 minutes) and instability at room temperature. The use of Treprostinil, a more stable alternative drug, has provided PAH patients with more treatment options. In 2021, clinical study data published in The Lancet Respiratory Medicine journal indicated that, for patients with interstitial lung disease and accompanying pulmonary arterial hypertension, inhaled Treprostinil improved patients' forced vital capacity (FVC) after 16 weeks compared to a placebo. This difference was most pronounced in patients with specific types of interstitial pneumonia, particularly those with Idiopathic Pulmonary Fibrosis. Inhaled Treprostinil appears to be a promising therapy for the treatment of Idiopathic Pulmonary Fibrosis. In 2021, multiple teams jointly initiated a phase III clinical trial of Treprostinil for the treatment of idiopathic pulmonary fibrosis. Nalbuphine is a κ-opioid receptor agonist and μ-opioid receptor antagonist that was originally researched and developed by Endo International plc. Currently, this medication is undergoing a Phase II clinical trial for Idiopathic Pulmonary Fibrosis (IPF). Brilaroxazine is a 5-HT1A/5-HT2A partial agonist originally researched and developed by Reviva Pharmaceuticals and is being used for the development of various clinical indications, including schizophrenia, idiopathic pulmonary fibrosis (IPF), and pulmonary arterial hypertension. Brilaroxazine has shown promising results in a Bleomycin-induced IPF rodent model when used alone or in combination with standard therapies. At present, this drug is also undergoing a Phase II clinical trial for IPF. Setogepram (PBI-4050) is a novel orally bioavailable small molecule compound developed by Liminal BioSciences. Its mechanism of action includes being an agonist for GPR40 and an antagonist for GPR84, demonstrating anti-fibrotic activity in various fibrosis models, including pulmonary fibrosis. Data from a 12-week Phase 2 clinical trial published in 2019 evaluated the safety, efficacy, and pharmacokinetics of daily oral administration of 800 mg of PBI-4050 alone or in combination with nintedanib or pirfenidone in patients with mild to moderate idiopathic pulmonary fibrosis (IPF). The 12-week open-label study investigated the effects of PBI-4050 in monotherapy in 9 patients, combined with nintedanib in 16 patients, and combined with nintedanib or pirfenidone in another 16 patients. The pharmacokinetic profiles were similar in both the PBI-4050 monotherapy group and the PBI-4050+nintedanib combination group, whereas the pharmacokinetics were reduced in the PBI-4050+pirfenidone group. There were no significant changes in Forced Vital Capacity (FVC) from baseline to week 12 in either the PBI-4050 monotherapy or the PBI-4050+nintedanib combination group. In contrast, a statistically significant decline in the percentage of predicted FVC was observed after 12 weeks of treatment with PBI-4050+pirfenidone. The stability of FVC between baseline and week 12 when using PBI-4050 alone or in combination with nintedanib was encouraging.

Study results identify NASH patients with Type 2 Diabetes as the key target population for Icosabutate therapy ICONA study assessed the safety, tolerability and efficacy of Icosabutate, a novel, dual FFAR1/FFAR4 (GPR40/GPR120) agonist in NASH patients with F1-F3 fibrosis. An increase in the proportion of patients achieving NASH resolution without worsening in fibrosis and a ≥2-point decrease in NAS was seen in the 600mg Icosabutate treated arm vs placebo (25.8% vs.11.9%, p=0.03), although the less stringent primary endpoint (not including NAS score) did not reach statistical significance in the overall study population. Significant treatment effect in diabetic NASH: In NASH patients with Type 2 diabetes (T2D), 600 mg Icosabutate significantly increased the proportion of patients achieving: NASH resolution without worsening of fibrosis (35.5% vs. 8.7% placebo, p=0.02) NASH resolution without worsening of fibrosis and ≥2-point decrease in NAS (35.5% vs. 4.3% placebo, p=0.007) ≥1-stage fibrosis improvement without worsening of NASH (19.4% vs. 0% placebo, p=0.02) Using AI technology, (qFibrosis, Histoindex) a 31% (p=0.03) treatment effect size was observed for regression of fibrosis stage in T2D patients treated with Icosabutate 600 mg. NorthSea will pursue a registrational development path for Icosabutate for the treatment of NASH patients with T2D. NorthSea to advance two additional clinical Phase 2 SEFA programs, i.e. SEFA-1024 for severe hypertriglyceridemia (SHTG) and SEFA-6179 for the orphan indication IFALD (Intestinal Failure Associated Liver Disease). AMSTERDAM--(BUSINESS WIRE)-- NorthSea Therapeutics B.V. (NST), a biotech company developing novel and innovative strategies for the treatment of non-alcoholic steatohepatitis (NASH) and other metabolic diseases, today announced that the results of the ICONA phase 2b study for the treatment of NASH, will be presented as an oral late-breaker at the AASLD Liver Meeting in Boston on November 13, 2023. The abstract, published today, describes that although the primary endpoint did not reach statistical significance, a significant increase in the proportion of patients achieving a more stringent endpoint, NASH resolution without worsening in fibrosis and a ≥2-point decrease in NAS, was seen in the 600 mg Icosabutate treated arm versus placebo (25.8% vs. 11.9%, p=0.03). A significant treatment effect size (31.2% placebo adjusted, p=0.007) was observed for the same endpoint in T2D patients. Based on the highly favorable response (both histological and non-invasive biomarkers) to therapy in T2D patients, NorthSea will pursue a registrational development path for Icosabutate in NASH patients with T2D. Professor Stephen Harrison, MD, consulting CMO, commented: “The high prevalence of NASH in patients with diabetes is well established. What is less well known is that subjects with both diabetes and NASH have a high prevalence of underlying significant liver fibrosis. Thus, there is a clear need for safe, well tolerated and efficacious therapies in this patient population that target both inflammation and fibrosis. Icosabutate’s mechanism of action, targeting FFAR1 and FFAR4, which regulate insulin secretion, insulin resistance and hepatic inflammation, provide biological rationale for the observed effects in diabetic patients. Overall, these study findings are highly promising with respect to the potential for Icosabutate as a backbone oral therapy for diabetic NASH.” Details of the ICONA Phase 2b data Two hundred and eighty patients were randomized in the ICONA trial, of which 178 per protocol patients met the histologic criteria (F1-3, NAS ≥ 4, ballooning ≥1, inflammation ≥1) based on a 3-member independent panel read. Patients were randomized 1:1:1 to receive once-daily, oral Icosabutate 300mg, Icosabutate 600mg or placebo for 52 weeks. The primary objective was to establish the proportion of patients with NASH resolution without worsening of fibrosis. Secondary objectives evaluated fibrosis improvement, as well as changes in markers of liver injury, inflammation, glycemic control, atherogenic lipids and safety and tolerability of Icosabutate. A subgroup analysis was performed in patients with T2D which comprised ~50% of the total population. The largest treatment effect was observed in patients with T2D, with 35.5% (p=0.007 vs. placebo) of T2D patients treated with Icosabutate 600 mg achieving NASH resolution and ≥2 point decrease in NAS compared to 4% in placebo-treated patients. For fibrosis improvement without worsening in NASH, 28.6% (p=0.005) and 19.4% (p=0.02) of T2D patients achieved a ≥1-stage improvement in the 300mg and 600mg arms respectively, versus none in placebo. A dose response in fibrosis stage regression (qFibrosis) was observed using AI technology (Histoindex) with a treatment effect size (placebo adjusted) in T2D patients of 13.7% (p=0.32) and 31% (p=0.03) in the 300mg and 600mg treatment arms respectively. Icosabutate markedly improved all markers of liver injury, inflammation, fibrosis, glycemic control (placebo corrected ~1% decrease in HbA1c in T2D patients with ≥6.5% at baseline), atherogenic lipids and hsCRP in a dose-dependent manner (Table 1). Both doses of Icosabutate were well tolerated. Change in markers of liver injury, inflammation and fibrosis in T2D patients1 Change from baseline Placebo (n=35) ICO 300mg (n=40) ICO 600mg (n=39) Relative change (%) in ALT -9.6 -33§§§ -42§§§ Relative change (%) in AST -16 -18§ -38§§§ Change in Enhanced Liver Fibrosis (ELF) Score (LS mean) -0.04 -0.06 -0.48§§§ Change in mean in Pro-C3 (ug/L) -2.86 -7.96§§§ -10.24§§§ Change in mean hsCRP (mg/L) 1.4 -1.1 -2.55* Change in HbA1c in T2D patients with ≥6.5% at baseline LS mean change from baseline Placebo (n=27) ICO 300mg (n=27) ICO 600mg (n=26) Change in HbA1c (%) absolute 0.35 -0.75* -0.61* Table 1. *p<0.05; §p<0.05, §§§p<0.001 vs baseline. 1All T2D subjects with baseline and 52 wk biopsies Arun Sanyal, Interim-Chair of the Division of Gastroenterology, Hepatology and Nutrition at VCU/VCU Health, added: “As is implied by the novel nomenclature, MASH (metabolic dysfunction associated steatohepatitis), metabolic dysfunction is an upstream driver of liver disease. The ability of Icosabutate to improve multiple markers of metabolic dysfunction, including insulin resistance, glycemic control, systemic inflammation and oxidative stress, are thus aligned with the improvements in histology and could potentially meet a key unmet need in MASH patients with type 2 diabetes”. Rob de Ree, CEO at NorthSea Therapeutics, said: “The ICONA trial is the first time that patients with NASH have been treated with Icosabutate. The significant improvements shown across both biomarker and histology parameters for patients with type 2 diabetes is important and, in our view, holds great promise. We believe that this data allows us to make a strong argument in favour of further clinical development of Icosabutate in Type 2 diabetes. The findings also validate the potential of targeting FFAR as a therapeutic approach for the treatment of diabetic NASH, either as monotherapy or in combination with other drugs in clinical development. We look forward to advancing Icosabutate as a safe, oral therapy for the treatment of diabetic NASH. In the meantime, we are pushing forward with the development of our other SEFA programmes.” Notes to Editors About NorthSea Therapeutics NorthSea Therapeutics B.V.(NST) is a Dutch biotech company focused on developing structurally engineered fatty acids (‘SEFAs’) for the treatment of NASH and other metabolic disorders. NST licensed the rights to its lead compound icosabutate and a library of SEFAs from Pronova BioPharma Norge AS, who developed Lovaza® (US brand, branded Omacor® in Europe), a blockbuster cardiometabolic drug. Icosabutate has been found safe and well tolerated in two prior phase 2 clinical studies for treatment of hypertriglyceridemia and mixed dyslipidemia and is currently in clinical development for NASH. Two additional SEFAs are in clinical development: SEFA-1024 has been developed for SHTG and now has entered Phase 2a; SEFA-6179, which completed a phase 1 study in Q4-2022, is being developed for the orphan indication IFALD (Intestinal Failure Associated Liver Disease). NST is headquartered in the Netherlands with a presence in Norway and the US and is supported by Ysios Capital, Forbion Growth, Forbion Ventures, Novo Holdings, BGV, NSV, venBio Partners and Sofinnova investments. Find out more about us online at: . SEFA-1024 SEFA-1024 is an oral, highly lipophilic SEFA for the treatment of severe hypertriglyceridemia that is designed to target the gut-liver axis and to concurrently improve plasma lipids and glycemic control. NST has concluded a Phase 1 clinical trial with single and multiple ascending doses and a drug-to-drug interaction study of SEFA-1024 in healthy volunteers with an excellent safety pro encouraging early signs of improvements in atherogenic lipids and lipoproteins. A Phase 2 proof-of-concept study started in H2 2023. SEFA-6179 NST is also developing SEFA-6179 – a novel, oral, fully synthetic medium chain fatty acid analogue – for the treatment of intestinal failure-associated liver disease, (IFALD), an orphan liver disease affecting individuals on prolonged parenteral nutrition. The unique pharmacologic properties of SEFA-6179 facilitate intestinal uptake, which is critical for ensuring optimal drug absorption in patients with intestinal failure and short bowel syndrome and has demonstrated strong anti-inflammatory and anti-cholestatic effect in pre-clinical parenteral nutrition induced liver injury models. A phase 1 single and multiple ascending dose study has been successfully completed. SEFA-6179 has advanced into Phase 2 in H2 2023.

LAVAL, QC and CAMBRIDGE, England, Sept. 15, 2023 /PRNewswire/ - Liminal BioSciences Inc. (NASDAQ: LMNL) ("Liminal BioSciences" or the "Company"), is pleased to announce that its shareholders have approved the previously-announced plan of arrangement under section 192 of the Canada Business Corporations Act (the "Arrangement") pursuant to which Structured Alpha LP ("SALP"), a limited partnership managed by its general partner, Thomvest Asset Management Ltd., will acquire all of the issued and outstanding common shares of Liminal BioSciences (the "Shares") not currently owned by SALP or its affiliates and associates at a price of US$8.50 per Share, payable in cash (the "Arrangement"). Further details regarding the Arrangement are described in the management information circular dated August 16, 2023 (the "Circular") mailed to Liminal BioSciences shareholders in connection with the Arrangement, as well as in the supplement to the Circular dated September 12, 2023, each of which is available under the Company's profile on SEDAR+ at and on EDGAR at . At a special meeting of the Company's shareholders held earlier today (the "Meeting"), the special resolution to approve the Arrangement was approved by approximately 98.82% of the votes cast by holders of Shares virtually present or represented by proxy at the Meeting, and by approximately 92.34% of the votes cast by holders of Shares virtually present or represented by proxy at the Meeting, excluding the votes of holders of Shares whose votes are required to be excluded for the purposes of "minority approval" under Multilateral Instrument 61-101 – Protection of Minority Security Holders in Special Transactions in the context of a "business combination", including the Shares over which SALP and its affiliates and associates exercise control or direction. A report on the voting results for the special meeting will be filed under the Company's profile on SEDAR+ at and on EDGAR at . The Arrangement remains subject to the satisfaction or waiver of certain other closing conditions customary in a transaction of this nature, including the receipt of a final order from the Ontario Superior Court of Justice (Commercial List) approving the Arrangement (the "Final Order"). The hearing in respect of the Final Order is scheduled to take place on September 19, 2023. Assuming that these remaining conditions to closing are satisfied, the Arrangement is expected to close at or around the end of September 2023. About Liminal BioSciences Inc. Liminal BioSciences is a development stage biopharmaceutical company focused on discovering and developing novel and distinctive small molecule therapeutics that modulate G protein-coupled receptors, or GPCR, pathways. Liminal BioSciences is designing proprietary novel small molecule therapeutic candidates with the intent of developing best/first in class therapeutics for the treatment of metabolic, inflammatory and fibrotic diseases with significant unmet medical needs, using our integrated drug discovery platform, medicinal chemistry expertise and deep understanding of the GPCR biology. Liminal BioSciences' pipeline is currently made up of three programs. The candidate selected for clinical development, LMNL6511, a selective antagonist for the GPR84 receptor, is expected to commence a Phase 1 clinical trial in the second half of 2023. Liminal BioSciences is also developing LMNL6326 as an antagonist for the OXER1 receptor, targeting treatment of eosinophil-driven disease, and GPR40 agonists, both of which are at the preclinical stage. In addition to these programs, Liminal BioSciences continues to explore other development opportunities to add to its pipeline. Liminal BioSciences has active business operations in Canada and the United Kingdom. About Structured Alpha LP Thomvest Asset Management Ltd. is the general partner of SALP. Thomvest Asset Management Ltd. and its affiliates are a group of investment companies that make investments on behalf of Peter J. Thomson and his family. Forward-Looking Statements This press release contains forward-looking statements within the meaning of Canadian and U.S. securities laws. Some of the forward-looking statements can be identified by the use of forward-looking words. Statements that are not historical in nature, including the words "anticipate," "expect," "suggest," "plan," "believe," "intend," "estimate," "target," "project," "should," "could," "would," "may," "will," "forecast" and other similar expressions are intended to identify forward-looking statements. These forward-looking statements generally include statements that are predictive in nature and depend upon or refer to future events or conditions, including, but not limited to statements related to Liminal BioSciences' business in general, the ability to complete and the timing of completion of the Arrangement and the other transactions contemplated by the arrangement agreement between Liminal BioSciences and SALP, including the parties' ability to satisfy the conditions to the consummation of the Arrangement and the possibility of any termination of the agreement. These statements are "forward-looking" because they are based on our current expectations about the markets we operate in and on various estimates and assumptions. Actual events or results may differ materially from those anticipated in these forward-looking statements if known or unknown risks affect our business, or if our estimates or assumptions turn out to be inaccurate. Among the factors that could cause actual results to differ materially from those described or projected herein include, but are not limited to, risks associated with: uncertainties with respect to the timing of the Arrangement; the risk that competing offers or acquisition proposals will be made; the possibility that various conditions to the consummation of the offer may not be satisfied or waived, including that a governmental entity may prohibit, delay or refuse to grant approval for the consummation of the Arrangement at all or on acceptable terms or within expected timing; the risk that stockholder litigation in connection with the Arrangement may result in significant costs of defense, indemnification and liability; the effects of disruption from the Arrangement on Liminal BioSciences' business and the fact that the announcement and pendency of the Arrangement may make it more difficult to establish or maintain relationships with employees and business partners; uncertainties associated generally with research and development, clinical trials and related regulatory reviews and approvals; Liminal BioSciences' ability to continue to comply with Nasdaq Listing Rule 5450(a)(1) to remain listed on Nasdaq; Liminal BioSciences' expected cash runway and Liminal BioSciences' ability to actively seek and close on opportunities to monetize non-core assets or commercial opportunities related to our assets; Liminal BioSciences' reliance on third parties to conduct, supervise and monitor existing clinical trials and potential future clinical trials; developments from Liminal BioSciences' competitors and the marketplace for Liminal BioSciences' product candidates; and business, operations and clinical development timelines and plans may be adversely affected by geopolitical events and macroeconomic conditions, including rising inflation and interest rates and uncertain credit and financial markets, and matters related thereto; and other risks and uncertainties affecting Liminal BioSciences, including in the Annual Report on Form 20-F for the year ended December 31, 2022, as well as other filings and reports Liminal BioSciences may make from time to time. As a result, we cannot guarantee that any given forward-looking statement will materialize. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements and estimates, which speak only as of the date hereof. We assume no obligation to update any forward-looking statement contained in this press release even if new information becomes available, as a result of future events or for any other reason, unless required by applicable securities laws and regulations. SOURCE Liminal BioSciences Inc.