Linaprazan glurate for the treatment of gastroesophageal reflux disease (GERD)

Abstract

The present invention relates to linapra angulate or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of gastrointestinal inflammatory or acid-related disorders, such as (erosive) gastroesophageal reflux disease. Treatment involves oral administration of linapra angulate or a pharmaceutically acceptable salt thereof to a subject once or twice daily in an amount of about 25 to about 100 mg.

Description

Technical Field

[0001] Cross-reference to Related Applications This application claims the priority of Swedish Patent Application No. 2330207-8, filed on May 8, 2023, the disclosure of which is hereby incorporated herein by reference in its entirety.

[0002] The present invention relates to linaprazan gluleate or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of gastrointestinal inflammatory or gastric acid-related diseases, such as erosive gastroesophageal reflux disease. The treatment comprises oral administration of linaprazan gluleate or a pharmaceutically acceptable salt thereof to a subject once or twice a day in an amount of about 25 to about 100 mg.

Background Art

[0003] Gastroesophageal reflux disease (GERD) is a digestive disease that affects the lower esophageal sphincter (a ring of muscle between the esophagus and the stomach), causing the contents of the stomach to reflux into the esophagus. Symptoms of GERD include tooth erosion, dysphagia, heartburn, acid reflux, non-cardiac chest pain, extraesophageal symptoms such as chronic cough, hoarseness, reflux-induced laryngitis, and asthma. If left untreated, GERD can cause complications such as esophagitis (inflammation of the esophagus), esophageal stricture, Barrett's esophagus (a condition in which the mucosal cells covering the lower part of the esophagus undergo abnormal (dysplastic) changes), dysplasia, and cancer (e.g., maltoma or adenocarcinoma).

[0004] It is estimated that 10% to 20% of Westerners suffer from GERD, but the prevalence is reported to be as high as 28% in the United States (El-Serag et al., Gut 2014, Vol. 63, pp. 871-880). In the United States and the EU30 countries, approximately 133 million adults suffer from reflux disease. While dietary and lifestyle changes may improve GERD symptoms, medical treatment with proton pump inhibitors (PPIs), H2 receptor blockers, or antacids is more effective. The global acid reflux disease market is dominated by PPIs, and it is estimated that more than 20% of all GERD patients take off-label PPIs twice daily to overcome incomplete symptom relief or to supplement treatment with commercially available medications. Despite the frequent off-label prescription of high-dose PPIs, many patients still suffer from inadequate symptom control. Therefore, there is a continuing need for better medications to treat GERD and provide effective symptom relief. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] WO 2021 / 089580 [Patent Document 2] WO 2023 / 185624 [Patent Document 3] US 2022 / 0002297 [Non-patent literature]

[0006] [Non-Patent Document 1] El-Serag et al., Gut 2014, Vol. 63, pp. 871-880. [Non-Patent Document 2] Yuan et al., Gastroenterol. 2007, Vol. 132(4), suppl. 2, A-489, No. T1202 [Non-Patent Document 3] Hunt, Aliment. Pharmacol. Ther. 1995, vol. 9, suppl. 1, pp. 3-7. [Non-Patent Document 4] Lundell et al., Gut 1999, Vol. 45, pp. 172-180 [Non-Patent Document 5] Andrae et al., Clin. Transl. Gastroenterol. 2020, 11(1): e00117 [Overview of the project]

[0007] Linapran angulate (5-{2-[({8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}carbonyl)-amino]ethoxy}-5-oxopentanoic acid, formerly known as X842) is a potassium-competitive acid blocker (P-CAB), a separate class of drugs under development for the treatment of GERD. P-CABs competitively inhibit the gastric hydrogen potassium pump (H+ / K+ ATPase) in parietal cells and have a considerably faster onset of maximal effect than PPIs (typically 1-2 hours vs. 3-5 days). In healthy subjects, neutral gastric pH has been demonstrated 2 hours after the first dose of linapran angulate. With a plasma half-life of approximately 10 hours, once or twice daily administration of linapran angulate is expected to result in 24-hour acid control. [Brief explanation of the drawing]

[0008] [Figure 1] This figure plots the cure rate (%) after 4 weeks against the average percentage of time (out of 24 hours) when gastric pH > 4 (based on Yuan et al., Gastroenterol. 2007, vol. 132(4), suppl. 2, A-489, No. T1202). [Figure 2] This figure shows a plot of gastric pH level versus linaprazan plasma concentration (nmol / L). At plasma concentrations above 240 nmol / L (striped area), gastric pH is almost always greater than 4. [Figure 3] This is a schematic diagram of the test design for the linapra angulate phase 1 preliminary dose setting study. [Figure 4] This is a schematic diagram of the study design for the LEED Dose Determination (LEAP) trial for linaprabraganglerate erosive esophagitis. [Figure 5] This figure plots the mean LA grade improvement after 4 weeks of treatment with different doses of linapra langurate (LG) or 30 mg of QD lansoprazole (LAN) in patients with LA grade C / D. [Figure 6] This figure plots the cure rate (%) after 4 weeks of treatment with different doses of linapraprazole langurate (LG) or 30 mg of QD lansoprazole (LAN) in patients with LA grade C / D. [Figure 7] This figure plots the cure rate (%) after 4 weeks of treatment with 75 mg BID linapra langurate (LG) or 30 mg QD lansoprazole (LAN) in patients with LA grade C / D. [Figure 8] This figure plots the cure rate (%) after 4 weeks of treatment with different doses of linapra langurate (LG) or 30 mg of QD lansoprazole (LAN) for all patients with LA grade A / B / C / D. [Figure 9] This figure shows a chart of mRESQ-eD scores, which assessed the number of heartburn-free 24-hour days per week during 8 weeks of treatment with different doses of linapra langurate (LG) or 30 mg of QD lansoprazole (LAN) for all patients. [Figure 10] This figure shows a chart of mRESQ-eD scores, which assessed the number of heartburn-free 24-hour days per week during 8 weeks of treatment with different doses of linapra langurate (LG) or 30 mg of QD lansoprazole (LAN) in all patients with LA grades A / B / C / D. [Figure 11] This figure shows a chart of mRESQ-eD scores, which assessed the number of heartburn-free 24-hour days per week during 8 weeks of treatment with different doses of linapra langurate (LG) or 30 mg of QD lansoprazole (LAN) in all LA grade C / D patients. [Figure 12]This is a diagram showing the X-ray powder diffraction pattern of form 1 of the HCl salt of linaprazan gurrate obtained from a slurry in DMF. [Figure 13] This is a diagram showing the differential scanning calorimetry (DSC) thermogram of form 1 of the HCl salt of linaprazan gurrate crystallized from DMF using EtOAc as an antisolvent. [Figure 14A] This is a diagram showing the dynamic vapour sorption (DVS) mass change plot of form 1 of the HCl salt of linaprazan gurrate crystallized from DMF using EtOAc as an antisolvent. [Figure 14B] This is a diagram showing the DVS isotherm plot of form 1 of the HCl salt of linaprazan gurrate crystallized from DMF using EtOAc as an antisolvent.

Mode for Carrying Out the Invention

[0009] In a first aspect, the present invention relates to linaprazan gurrate or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of gastrointestinal inflammatory or gastric acid-related diseases, which is orally administered to a subject once or twice a day in an amount of about 25 to about 100 mg.

[0010] Clinical trials have shown that treatment of eGERD for 4 weeks with linaprazan gurrate at 25, 50, 75, or 100 mg twice a day results in a high cure rate. Interestingly, such treatment has been found to give better results than treatment with the proton pump inhibitor (PPI) lansoprazole, which is currently the standard care treatment. As shown in the Examples section, 4 weeks of treatment with linaprazan gurrate resulted in a significantly higher cure rate than treatment with lansoprazole at 30 mg / day.

[0011] In some embodiments, lenaprazan gluco rate or a pharmaceutically acceptable salt thereof is administered once daily (QD). In some embodiments, lenaprazan gluco rate or a pharmaceutically acceptable salt thereof is administered twice daily (BID). Administration of lenaprazan gluco rate twice daily has been found to be approximately 10% (about 2 hours) longer in the time per day that gastric pH > 4 compared to administration of lenaprazan gluco rate once daily. The 24-hour pH median and the % of time during 24 hours that pH > 4 are excellent predictors of healing at 8 weeks of erosive esophagitis, and it has been previously reported that the better the acid suppression (pH > 4), the better the efficacy in healing esophagitis (Hunt, Aliment. Pharmacol. Ther. 1995, Vol. 9, suppl. 1, pp. 3-7; Yuan et al., Gastroenterol. 2007, Vol. 132(4), suppl. 2, A-489, No T1202). A plot of the healing rate (%) after 4 weeks versus the mean percentage of time with gastric pH > 4 is shown in FIG. 1. Administration of lenaprazan gluco rate twice daily can thus provide better results than administration of lenaprazan gluco rate once daily in the treatment of gastrointestinal inflammatory or gastric acid-related diseases.

[0012] After absorption into the bloodstream, lenaprazan gluco rate is rapidly metabolized to the active metabolite lenaprazan. The plasma concentration of lenaprazan gluco rate is extremely low and difficult to determine, but instead the plasma concentration of lenaprazan can be determined. Phase I studies have shown that the pH control of lenaprazan gluco rate is dose-dependent and that a minimum plasma concentration (Cmin) of lenaprazan of about 240 nmol / L is essential to maintain gastric pH above 4 (see FIG. 2).

[0013] Accordingly, in some embodiments, the present invention relates to linapragrangurate or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of gastrointestinal inflammatory or gastric acid-related diseases, wherein, after oral administration of linapragrangurate or a pharmaceutically acceptable salt thereof to a subject in an amount of about 25 to about 100 mg once or twice daily, the subject exhibits a minimum plasma concentration (Cmin) of linaprazan of at least 240 nmol / L.

[0014] In some embodiments, linapra angulate or a pharmaceutically acceptable salt thereof is administered once or twice daily in amounts of about 25 to about 100 mg, for example, about 25 to about 75 mg, for example, about 25 to about 50 mg, for example, about 50 to about 100 mg, for example, about 50 to about 75 mg, or for example, about 75 to about 100 mg. In some embodiments, linapra angulate or a pharmaceutically acceptable salt thereof is administered once daily in amounts of about 25 mg. In some embodiments, linapra angulate or a pharmaceutically acceptable salt thereof is administered twice daily in amounts of about 25 mg. In some embodiments, linapra angulate or a pharmaceutically acceptable salt thereof is administered once daily in amounts of about 50 mg. In some embodiments, linapra angulate or a pharmaceutically acceptable salt thereof is administered twice daily in amounts of about 50 mg. In some embodiments, linapra angulate or a pharmaceutically acceptable salt thereof is administered once daily at a dose of approximately 75 mg. In some embodiments, linapra angulate or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of approximately 75 mg. In some embodiments, linapra angulate or a pharmaceutically acceptable salt thereof is administered once daily at a dose of approximately 100 mg. In some embodiments, linapra angulate or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of approximately 100 mg.

[0015] In some embodiments, linapra angulate or a pharmaceutically acceptable salt thereof is administered at least 30 minutes before a meal.

[0016] In some embodiments, linapra angulate or a pharmaceutically acceptable salt thereof is administered as needed. In some embodiments, linapra angulate or a pharmaceutically acceptable salt thereof is administered for at least one week. In some embodiments, linapra angulate or a pharmaceutically acceptable salt thereof is administered for at least two weeks. In some embodiments, linapra angulate or a pharmaceutically acceptable salt thereof is administered for at least three weeks. In some embodiments, linapra angulate or a pharmaceutically acceptable salt thereof is administered for at least four weeks. In some embodiments, linapra angulate or a pharmaceutically acceptable salt thereof is administered for at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, or at least ten weeks.

[0017] In some embodiments, linapra angulate or a pharmaceutically acceptable salt thereof is administered twice daily for 4 weeks at a dose of approximately 25 to approximately 100 mg.

[0018] In some embodiments, gastrointestinal inflammatory disease or acid-related disorder is gastritis, gastroesophageal reflux disease (GERD), erosive gastroesophageal reflux disease (eGERD), Helicobacter pylori infection, Zollinger-Ellison syndrome, peptic ulcer disease (including gastric and duodenal ulcers), hemorrhagic gastric ulcer, symptoms of gastroesophageal reflux disease (including heartburn, reflux, and nausea), gastrinoma, acute upper gastrointestinal bleeding, or injury or bleeding caused by aspirin or NSAIDs. In some embodiments, gastrointestinal inflammatory disease or acid-related disorder is gastroesophageal reflux disease (GERD). In some embodiments, gastrointestinal inflammatory disease or acid-related disorder is erosive gastroesophageal reflux disease (eGERD).

[0019] The severity of esophagitis is typically indicated using the Los Angeles (LA) classification of reflux esophagitis, which is based on the patient's endoscopic assessment. The LA grading system divides reflux esophagitis into four categories (LA grades A-D) based on the degree of esophageal mucosal damage. LA grade A esophagitis, the mildest form, is defined as one or more mucosal lesions of 5 mm or less that do not reach between the apexes of two mucosal folds. LA grade B esophagitis is defined as one or more mucosal lesions of 5 mm or more that do not reach between the apexes of two mucosal folds. LA grade C esophagitis is defined as one or more mucosal lesions that extend to the apexes of two mucosal folds but include less than 75% of the periphery of the esophagus. The most severe form, LA-grade D esophagitis, is defined as damage to one or more mucous membranes, including at least 75% of the area surrounding the esophagus (Lundell et al., Gut 1999, vol. 45, pp. 172-180).

[0020] In some embodiments, GERD or eGERD is LA grade A. In some embodiments, GERD or eGERD is LA grade B. In some embodiments, GERD or eGERD is LA grade C. In some embodiments, GERD or eGERD is LA grade D.

[0021] In some embodiments, the subject exhibits improvement in the LA grade of reflux esophagitis after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof. Herein, the terms “LA grade improvement” and “LA grade improvement” refer to one or more steps from one LA grade to a lower LA grade (e.g., from grade D to grade C, B, or A), or to a complete cure. In some embodiments, the LA grade improvement is one step. In some embodiments, the LA grade improvement is two steps. In some embodiments, the LA grade improvement is three steps. In some embodiments, the LA grade improvement is four steps.

[0022] In some embodiments, the mean LA grade improvement is at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2.0, at least 2.1, at least 2.2, at least 2.3, at least 2.4, at least 2.5, at least 2.6, at least 2.7, at least 2.8, at least 2.9, at least 3.0, at least 3.1, at least 3.2, at least 3.3, at least 3.4, or at least 3.5 after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof in amounts of about 25 to about 100 mg twice daily for at least 1, 2, 3, or 4 weeks.

[0023] In some embodiments, the subject heals after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof for at least 1, 2, 3, or 4 weeks. In some embodiments, the subject heals after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 25 to about 100 mg twice daily for 4 weeks.

[0024] In some embodiments, GERD or eGERD is LA grade A, and the subject shows a one-step improvement in LA grade after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 25 to about 100 mg once or twice daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade A, and the subject shows a one-step improvement in LA grade after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 25 mg once daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade A, and the subject shows a one-step improvement in LA grade after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 25 mg twice daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade A, and the subject shows a one-step improvement in LA grade after oral administration of approximately 50 mg of linapra angulate or a pharmaceutically acceptable salt thereof once daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade A, and the subject shows a one-step improvement in LA grade after oral administration of approximately 50 mg of linapra angulate or a pharmaceutically acceptable salt thereof twice daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade A, and the subject shows a one-step improvement in LA grade after oral administration of approximately 75 mg of linapra angulate or a pharmaceutically acceptable salt thereof once daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade A, and the subject shows a one-step improvement in LA grade after oral administration of approximately 75 mg of linapra angulate or a pharmaceutically acceptable salt thereof twice daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade A, and the subject shows a one-step improvement in LA grade after oral administration of approximately 100 mg of linapra angulate or a pharmaceutically acceptable salt thereof once daily for at least 1, 2, 3, or 4 weeks.In some embodiments, GERD or eGERD is LA grade A, and the subject shows a one-step improvement in LA grade after oral administration of approximately 100 mg of linapra angulate or a pharmaceutically acceptable salt thereof twice daily for at least 1, 2, 3, or 4 weeks. Subjects showing a one-step improvement in LA grade A are considered cured.

[0025] In some embodiments, GERD or eGERD is LA grade B, and the subject shows a 1 or 2-step, more preferably 2-step, improvement in LA grade after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 25 to about 100 mg once or twice daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade B, and the subject shows a 1 or 2-step, more preferably 2-step, improvement in LA grade after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 25 mg once daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade B, and the subject shows a 1 or 2-step, more preferably 2-step, improvement in LA grade after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 25 mg twice daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade B, and the subject shows a 1 or 2-step, more preferably 2-step, improvement in LA grade after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 50 mg once daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade B, and the subject shows a 1 or 2-step, more preferably 2-step, improvement in LA grade after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 50 mg twice daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade B, and the subject shows a 1 or 2-step, more preferably 2-step, improvement in LA grade after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 75 mg once daily for at least 1, 2, 3, or 4 weeks. In some embodiments, the GERD or eGERD is LA grade B, and the subject shows an improvement of one or two, more preferably two, levels in the LA grade after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 75 mg twice daily for at least one, two, three, or four weeks.In some embodiments, GERD or eGERD is LA grade B, and the subject shows a 1 or 2-step, more preferably 2-step, improvement in LA grade after oral administration of approximately 100 mg of linapra angulate or a pharmaceutically acceptable salt thereof once daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade B, and the subject shows a 1 or 2-step, more preferably 2-step, improvement in LA grade after oral administration of approximately 100 mg of linapra angulate or a pharmaceutically acceptable salt thereof twice daily for at least 1, 2, 3, or 4 weeks. LA grade B subjects showing a 2-step improvement in LA grade are considered cured.

[0026] In some embodiments, GERD or eGERD is LA grade C, and the subject shows an LA grade improvement of 1, 2, or 3 steps, more preferably 2 or 3 steps, most preferably 3 steps, after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof in an amount of about 25 to about 100 mg once or twice daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade C, and the subject shows an LA grade improvement of 1, 2, or 3 steps, more preferably 2 or 3 steps, most preferably 3 steps, after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 25 mg twice daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade C, and the subject shows an LA grade improvement of 1, 2, or 3 steps, more preferably 2 or 3 steps, most preferably 3 steps, after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 50 mg once daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade C, and the subject shows an LA grade improvement of 1, 2, or 3 steps, more preferably 2 or 3 steps, most preferably 3 steps, after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 50 mg twice daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade C, and the subject shows an LA grade improvement of 1, 2, or 3 steps, more preferably 2 or 3 steps, most preferably 3 steps, after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 75 mg once daily for at least 1, 2, 3, or 4 weeks.In some embodiments, GERD or eGERD is LA grade C, and the subject shows an LA grade improvement of 1, 2, or 3 steps, more preferably 2 or 3 steps, most preferably 3 steps, after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 75 mg twice daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade C, and the subject shows an LA grade improvement of 1, 2, or 3 steps, more preferably 2 or 3 steps, most preferably 3 steps, after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 100 mg once daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade C, and the subject shows an improvement in LA grade of 1, 2, or 3, more preferably 2 or 3, and most preferably 3, after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 100 mg twice daily for at least 1, 2, 3, or 4 weeks. An LA grade C subject showing a 3-step improvement in LA grade is considered cured.

[0027] In some embodiments, GERD or eGERD is LA grade D, and the subject shows an LA grade improvement of 1, 2, 3, or 4 steps, more preferably 2, 3, or 4 steps, even more preferably 3 or 4 steps, most preferably 4 steps, after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 25 mg once or twice daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade D, and the subject shows an LA grade improvement of 1, 2, 3, or 4 steps, more preferably 2, 3, or 4 steps, even more preferably 3 or 4 steps, most preferably 4 steps, after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 25 mg twice daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade D, and the subject shows an LA grade improvement of 1, 2, 3, or 4 steps, more preferably 2, 3, or 4 steps, even more preferably 3 or 4 steps, most preferably 4 steps, after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 50 mg once daily for at least 1, 2, 3, or 4 weeks. In some embodiments, the GERD or eGERD is LA grade D, and the subject shows an improvement in LA grade of 1, 2, 3, or 4 steps, more preferably 2, 3, or 4 steps, even more preferably 3 or 4 steps, and most preferably 4 steps, after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 50 mg twice daily for at least 1, 2, 3, or 4 weeks.In some embodiments, GERD or eGERD is LA grade D, and the subject shows an LA grade improvement of 1, 2, 3, or 4 steps, more preferably 2, 3, or 4 steps, even more preferably 3 or 4 steps, most preferably 4 steps, after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 75 mg once daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade D, and the subject shows an LA grade improvement of 1, 2, 3, or 4 steps, more preferably 2, 3, or 4 steps, even more preferably 3 or 4 steps, most preferably 4 steps, after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 75 mg twice daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade D, and the subject shows an LA grade improvement of 1, 2, 3, or 4 steps, more preferably 2, 3, or 4 steps, even more preferably 3 or 4 steps, most preferably 4 steps, after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 100 mg once daily for at least 1, 2, 3, or 4 weeks. In some embodiments, GERD or eGERD is LA grade D, and the subject shows an LA grade improvement of 1, 2, 3, or 4 steps, more preferably 2, 3, or 4 steps, even more preferably 3 or 4 steps, most preferably 4 steps, after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof at a dose of about 100 mg twice daily for at least 1, 2, 3, or 4 weeks. An LA grade D subject showing a 4-step LA grade improvement is considered cured.

[0028] In some embodiments, subjects demonstrate a reduction in reflux-related symptoms after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof. In some embodiments, subjects demonstrate an increase in the number of 24-hour days with at most mild symptoms. In some embodiments, subjects demonstrate an increase in the number of 24-hour days without heartburn. The reduction in reflux-related symptoms can be assessed based on the Reflux Symptom Reflux Questionnaire-electronic Diary (mRESQ-eDiary), an electronic symptom diary developed for use in patients with partial responses to proton pump inhibitors. The mRESQ-eDiary has three domains (i.e., heartburn, other GERD signs / symptoms, and regurgitation / reflux) and eight items (Andrae et al., Clin. Transl. Gastroenterol. 2020, 11(1): e00117).

[0029] In some embodiments, the subject has at least about 55% of 24 hours free from heartburn over a week, for example, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% of 24 hours free from heartburn over a week. In some embodiments, the subject has at least about 95% of 24 hours free from heartburn over a week.

[0030] A method for treating or preventing gastrointestinal inflammatory or acid-related disorders in subjects requiring such treatment is also provided, comprising the step of orally administering linapra angulate or a pharmaceutically acceptable salt thereof to a subject in an amount of about 25 to about 100 mg once or twice daily. A use of linapra angulate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of gastrointestinal inflammatory or acid-related disorders is also provided, wherein linapra angulate or a pharmaceutically acceptable salt thereof is orally administered in an amount of about 25 to about 100 mg once or twice daily.

[0031] In some embodiments, the present invention relates to a pharmaceutical formulation comprising linapra angulate or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of gastrointestinal inflammatory or gastric acid-related diseases, wherein the pharmaceutical formulation contains linapra angulate or a pharmaceutically acceptable salt thereof in an amount of about 25 to about 100 mg and is administered orally once or twice daily to the subject.

[0032] formulation Linapra angulate or a pharmaceutically acceptable salt thereof can be administered to subjects, for example, in the form of tablets or capsules.

[0033] Preparations of linapra angulate or a pharmaceutically acceptable salt thereof comprise a therapeutically effective amount of linapra angulate or a pharmaceutically acceptable salt thereof in association with one or more pharmaceutically acceptable excipients. Excipients may include, for example, fillers, binders, surfactants, disintegrants, flow enhancers, and lubricants.

[0034] In some embodiments, the formulation includes a surfactant. The surfactant may be a cationic surfactant, anionic surfactant, or nonionic surfactant. Examples of cationic surfactants include, but are not limited to, cetyltrimethylammonium bromide (cetrimonium bromide) and cetylpyridinium chloride. Examples of anionic surfactants include, but are not limited to, sodium dodecyl sulfate (sodium lauryl sulfate) and ammonium dodecyl sulfate (ammonium lauryl sulfate). Examples of nonionic surfactants include, but are not limited to, glycerol monooleate, glycerol monostearate, polyoxyl castor oil (Cremophor EL), poloxamer (e.g., poloxamer 407 or 188), polysorbate 80, and sorbitan ester (Tween). In some embodiments, the surfactant is anionic. In preferred embodiments, the anionic surfactant is sodium dodecyl sulfate.

[0035] The surfactant may be present in the formulation in an amount of about 1.0% (w / w) relative to the amount of linapra angulate or its pharmaceutically acceptable salt, for example, about 2.0 to about 12.0% (w / w), for example, about 4.0 to about 12.0% (w / w), for example, about 6.0 to about 12.0% (w / w), for example, about 8.0 to about 12.0% (w / w), or for example, about 10.0 to about 12.0% (w / w), relative to the amount of linapra angulate or its pharmaceutically acceptable salt. The amount of surfactant in the formulation is preferably as small as possible. Therefore, in another embodiment, the formulation contains about 1.0 to about 11.0% (w / w), for example, about 1.0 to about 10.0% (w / w), for example, about 1.0 to about 9.0% (w / w), for example, about 1.0 to about 8.0% (w / w), or for example, about 1.0 to about 7.0% (w / w), relative to the amount of linapra angullate or a pharmaceutically acceptable salt thereof, of surfactant. In another embodiment, the formulation contains about 2.0 to about 11.0% (w / w), for example, about 2.0 to about 10.0% (w / w), for example, about 2.0 to about 9.0% (w / w), for example, about 2.0 to about 8.0% (w / w), or for example, about 2.0 to about 7.0% (w / w), relative to the amount of linapra angullate or a pharmaceutically acceptable salt thereof, of surfactant. In yet another embodiment, the formulation contains a surfactant in an amount of about 4.0 to about 11.0% (w / w), for example, about 4.0 to about 10.0% (w / w), for example, about 4.0 to about 9.0% (w / w), for example, about 4.0 to about 8.0% (w / w), or for example, about 4.0 to about 7.0% (w / w), relative to the amount of linapra angulate or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, the formulation contains a surfactant in an amount of about 11.0% (w / w) or less relative to the amount of linapra angulate or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation contains a surfactant in an amount of about 10.0% (w / w) or less relative to the amount of linapra angulate or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation contains a surfactant in an amount of about 9.0% (w / w) or less relative to the amount of linapra angulate or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation contains a surfactant in an amount of about 8.0% (w / w) or less relative to the amount of linapra angulate or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, the formulation includes a filler. Suitable fillers include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose (e.g., lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, dry starch, hydrolyzed starch, and pregelatinized starch. In some embodiments, the filler is lactose, for example, lactose monohydrate.

[0038] In some embodiments, the formulation includes a binder. Suitable binders include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (e.g., sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycol, wax, natural and synthetic rubbers (e.g., acacia rubber and tragacanth rubber), sodium alginate, cellulose derivatives (e.g., hydroxypropyl methylcellulose (or hypromellose), hydroxypropyl cellulose, and ethyl cellulose), and synthetic polymers (e.g., acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid copolymers, and polyvinylpyrrolidone (povidone)).

[0039] In some embodiments, the formulation includes a disintegrant. Suitable examples of disintegrants include, but are not limited to, dry starch, modified starch (e.g., (partially) pregelatinized starch, sodium starch glycolate, and sodium carboxymethyl starch), alginic acid, cellulose derivatives (e.g., sodium carboxymethylcellulose, hydroxypropylcellulose, and low-substituted hydroxypropylcellulose (L-HPC)), and crosslinked polymers (e.g., carmellose, croscarmellose sodium, carmellose calcium, and crosslinked PVP (crospovidone)). In some embodiments, the disintegrant is croscarmellose sodium.

[0040] In some embodiments, the formulation includes a flow promoter or lubricant. Suitable examples of flow promoters and lubricants include, but are not limited to, talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, colloidal anhydrous silica, aqueous silicon dioxide, synthetic magnesium silicate, fine-grained silicon dioxide, starch, sodium lauryl sulfate, boric acid, magnesium oxide, wax (e.g., carnauba wax), hydrogenated oil, polyethylene glycol, sodium benzoate, polyethylene glycol, and mineral oil. In certain embodiments, the flow promoter is colloidal anhydrous silica.

[0041] Pharmaceutical formulations of linapra angulate are disclosed, for example, in WO 2021 / 089580 and WO 2023 / 185624. In some embodiments, tablet formulations of linapra angulate have the compositions shown in Table 1.

[0042] [Table 1]

[0043] Generally, formulations can be prepared in conventional methods using conventional excipients. In some embodiments, the components of a formulation are mixed into a homogeneous mixture and then formulated as tablets or capsules. The homogeneous mixture of components can be compressed into tablets using conventional techniques such as a rotary tablet press. The mixture of components may also be granulated. For example, the mixture of components can be moistened by adding a liquid such as water and / or a suitable organic solvent (e.g., ethanol or isopropanol), then granulated and dried. Alternatively, granules can be prepared by dry granulation such as roller compression. The resulting granules can be compressed into tablets using conventional techniques. Capsules may contain a powder mixture of components or small multiparticulates (e.g., granules, extruded pellets, or minitablets). Where desired, any of the above-mentioned tablets, capsules, granules, extruded pellets, and minitablets can be coated with one or more coating layers. Such coating layers can be applied by methods known in the art, such as film coatings including perforated pans and fluidized beds. In some embodiments, the formulation is in the form of a tablet.

[0044] Salt and crystalline form In some embodiments, linapra angulate or a pharmaceutically acceptable salt thereof exists in a crystalline form. In some embodiments, linapra angulate exists as a crystalline anhydride, as disclosed in US 2022 / 0002297. In certain embodiments, the crystalline anhydride of linapra angulate is form A.

[0045] In a specific embodiment, form A has an X-ray powder diffraction (XRPD) pattern obtained using CuKα1 rays, having at least peaks at °2θ values ​​of 9.9±0.2 and 11.5±0.2. In a more specific embodiment, form A has an X-ray powder diffraction pattern obtained using CuKα1 rays, having at least peaks at 9.9±0.2 and 11.5±0.2, and one or more of 8.4±0.2, 15.5±0.2, and 16.8±0.2.

[0046] In a more specific embodiment, form A has an XRPD pattern obtained using CuKα1 rays, having at least peaks at the °2θ values ​​of 8.4±0.2, 9.9±0.2, 11.5±0.2, 15.5±0.2, 16.8±0.2, 23.5±0.2, 24.9±0.2, and 25.5±0.2.

[0047] In a more specific embodiment, form A has an XRPD pattern obtained using CuKα1 rays, having at least one or more °2θ values ​​with peaks at 8.4±0.2, 9.9±0.2, 11.5±0.2, 15.5±0.2, 16.8±0.2, 23.5±0.2, 24.9±0.2, and 25.5±0.2, as well as 18.2±0.2, 18.4±0.2, 21.0±0.2, 21.2±0.2, and 23.3±0.2.

[0048] In some embodiments, linapra angulate exists as a pharmaceutically acceptable salt of linapra angulate. Suitable examples of pharmaceutically acceptable salts of linapra angulate include, but are not limited to, hydrochloride, hydrobromide, methanesulfonate ("mesylate"), or maleate ("maleate"). In some embodiments, linapra angulate exists as a hydrochloride of linapra angulate.

[0049] In some embodiments, linapra angulate exists as a crystalline hydrochloride of linapra angulate, as disclosed in WO 2023 / 079094.

[0050] In some embodiments, linapra angulate exists as a crystalline HCl salt of linapra angulate, which is stable at room temperature and 94% relative humidity (RH). Such crystalline HCl salts may remain stable under these conditions for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, 2 years, 3 years, or even longer.

[0051] In some embodiments, linapra angulate exists as a crystalline anhydride of the HCl salt of linapra angulate. In certain embodiments, the crystalline anhydride of the HCl salt of linapra angulate is Form 1. This stable form can be prepared directly from the free base of linapra angulate or by certain crystallization techniques using its hydrochloride salt, for example, from a slurry in DMF, pyridine, benzyl alcohol, or ethanol; by reverse solvent crystallization from DMF or pyridine and a specific reverse solvent; or by cooling from DMF or pyridine.

[0052] In a specific embodiment, form 1 of the HCl salt of linapran angulate has an X-ray powder diffraction (XRPD) pattern obtained using CuKα1 rays, which has at least two peaks at °2θ values ​​selected from a list consisting of 9.1±0.2, 13.8±0.2, 14.0±0.2, 20.0±0.2, 22.9±0.2, 23.4±0.2, 24.4±0.2, 24.6±0.2, and 26.7±0.2.

[0053] In a more specific embodiment, form 1 of the HCl salt of linapran angulate has an XRPD pattern obtained using CuKα1 lines, which has at least peaks at °2θ values ​​of 20.0±0.2 and 26.7±0.2.

[0054] In a more specific embodiment, form 1 of the HCl salt of linapran angulate has an XRPD pattern having at least four peaks at °2θ values ​​selected from a list consisting of 9.1±0.2, 13.8±0.2, 14.0±0.2, 20.0±0.2, 22.9±0.2, 23.4±0.2, 24.4±0.2, 24.6±0.2, and 26.7±0.2, obtained using CuKα1 lines.

[0055] In a more specific embodiment, form 1 of the HCl salt of linapran angulate has an XRPD pattern obtained using CuKα1 lines, which has peaks at least at °2θ values ​​of 20.0±0.2, 24.4±0.2, 24.6±0.2, and 26.7±0.2.

[0056] In a more specific embodiment, form 1 of the HCl salt of linapran angulate has an XRPD pattern obtained using CuKα1 lines, having at least one or more °2θ values ​​among 20.0±0.2, 24.4±0.2, 24.6±0.2, and 26.7±0.2, and 9.1±0.2, 13.8±0.2, 14.0±0.2, 22.9±0.2, and 23.4±0.2.

[0057] In a more specific embodiment, form 1 of the HCl salt of linapran angulate has an XRPD pattern obtained using CuKα1 lines, having at least peaks at °2θ values ​​of 9.1±0.2, 13.8±0.2, 20.0±0.2, 23.4±0.2, 24.4±0.2, 24.6±0.2, and 26.7±0.2.

[0058] In a more specific embodiment, form 1 of the HCl salt of linapran angulate has an XRPD pattern obtained using CuKα1 lines, having at least peaks at °2θ values ​​of 9.1±0.2, 13.8±0.2, 14.0±0.2, 20.0±0.2, 22.9±0.2, 23.4±0.2, 24.4±0.2, 24.6±0.2, and 26.7±0.2.

[0059] In a more specific embodiment, form 1 of the HCl salt of linapran angulate has an XRPD pattern obtained using CuKα1 lines, having at least one or more peaks at °2θ values ​​among 9.1±0.2, 13.8±0.2, 14.0±0.2, 20.0±0.2, 22.9±0.2, 23.4±0.2, 24.4±0.2, 24.6±0.2, and 26.7±0.2, and 16.2±0.2, 18.6±0.2, 22.2±0.2, 25.6±0.2, and 27.9±0.2.

[0060] In another embodiment, form 1 of the HCl salt of linapran angulate has an XRPD pattern obtained using CuKα1 lines, substantially as shown in Figure 12.

[0061] In another embodiment, form 1 of the HCl salt of linapran angulate has a DSC curve that includes endothermic heating between approximately 230°C and approximately 240°C. In a particular embodiment, form 1 of the HCl salt of linapran angulate has a DSC curve that includes endothermic heating at approximately 233°C. The DSC thermogram of form 1 of the HCl salt of linapran angulate is shown in Figure 13.

[0062] Dynamic vapor sorption analysis revealed that form 1 of the HCl salt of linapran angulate has very low hygroscopicity, with water uptake of only about 0.2% at 90% RH. Mass change plots and sorption isotherm plots of form 1 of the HCl salt of linapran angulate showed very little water uptake at increased humidity; see Figures 14A and 14B, respectively. This low hygroscopicity is considered advantageous because the water content of the crystals remains substantially constant even when humidity changes within the normal relative humidity range of about 30% to about 80% RH. In some embodiments, form 1 of the HCl salt of linapran angulate is stable at relative humidity up to 90% at a temperature of 25°C.

[0063] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention pertains. Methods and substances are described herein for use in the present invention; other suitable methods and substances known in the art may also be used. Substances, methods, and examples are illustrative and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references referenced herein are incorporated in their entirety by reference. In case of any conflict, including definitions, this specification shall prevail.

[0064] In this specification, the terms “effective dose” or “therapeutic effective dose” refer to the amount of linapra angulate or a pharmaceutically acceptable salt thereof that, after administration to a subject, is sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated. The results include reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desirable changes in the biological system. For example, “effective dose” for therapeutic use is the amount of linapra angulate or a pharmaceutically acceptable salt thereof required to produce a clinically significant reduction in disease symptoms. The appropriate “effective” dose in any individual case is determined using any appropriate technique, such as dose escalation studies.

[0065] In this specification, the terms “treatment,” “treat,” and “treating” refer to the disease or disorder described herein, or to reversing, alleviating, delaying the onset, or inhibiting the progression of one or more of their symptoms. In some embodiments, treatment can be performed after the onset of one or more symptoms. In other embodiments, treatment can be performed when there are no symptoms. For example, treatment can be performed on a susceptible individual before the onset of symptoms (e.g., taking into account a history of symptoms and / or genetic or other susceptibility factors). Treatment can also be continued after the symptoms have resolved, for example, to prevent or delay their recurrence.

[0066] In this specification, the terms “subject,” “individual,” or “patient” as used interchangeably refer to any animal, including mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and mammals such as humans. In some embodiments, the subject is a human.

[0067] In this specification, the term “pharmaceutically acceptable” means a compound, substance, composition, and / or dosage form that is suitable for human pharmaceutical use, is generally safe, non-toxic, and is not biologically or otherwise undesirable.

[0068] In this specification, the terms “twice daily” or “BID” (bis in die) refer to the administration of a drug at two different times of day, for example, at intervals of at least about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours. In some embodiments, twice daily refers to once in the morning and once in the evening. The administration of two or more unit doses of a drug (e.g., pills, tablets, or capsules) at one time of day is considered once daily, while the administration of two or more unit doses of a drug (e.g., pills, tablets, or capsules) at two different times of day is considered twice daily.

[0069] In this specification, the term “about” refers to a value or parameter in this specification, including (and described) embodiments that apply to that value or parameter itself. For example, a statement referring to “about 20” includes the statement “20.” A numerical range includes the digits that define that range. Generally, the term “about” refers to all values ​​of a variable that are within the indicated value and the experimental error of the indicated value (e.g., within the 95% confidence interval of the mean) or within 10 percent of the indicated value, whichever is greater.

[0070] In this specification, the terms “crystalline form” or “polymorph” refer to crystals of the same molecule that have different physical properties as a result of the order of molecules in the crystal lattice. Polymorphs of a single compound have one or more distinct chemical, physical, mechanical, electrical, thermodynamic, and / or biological properties. Differences in physical properties exhibited by polymorphisms can affect pharmaceutical parameters such as storage stability, compressibility, density (important in the manufacture of compositions and products), dissolution rate (an important factor in determining bioavailability), solubility, melting point, chemical stability, physical stability, powder flowability, water sorption, compressibility, and particle morphology. Differences in stability can result from changes in chemical reactivity (e.g., differences in oxidation, such as a dosage form changing color more rapidly when composed of one polymorph than when composed of another), mechanical changes (e.g., crystalline changes during storage when a kinetically favorable polymorph is converted to a thermodynamically more stable polymorph), or both (e.g., one polymorph is more hygroscopic than another). As a result of differences in solubility / dissolution, some transitions affect potency and / or toxicity. Furthermore, the physical properties of the crystals can be important in processing; for example, some polymorphs may readily form solvates or be difficult to filter and wash to remove impurities (i.e., particle shape and size distribution may differ between polymorphs). "Polymorph" does not include amorphous forms of the compound.

[0071] In this specification, the terms “anhydrous” or “anhydrous form” refer to the crystalline form of linapra angulate or its pharmaceutically acceptable salt having 0.5% by mass or less of water, for example, 0.4% by mass or less, 0.3% by mass or less, 0.2% by mass or less, or 0.1% by mass or less of water.

[0072] In this specification, the term “stable” means that the crystalline form (i.e., polymorph) does not show any change over time in one or more of the following: polymorphic form (e.g., increase or decrease in a particular form), appearance, pH, impurity percentage, activity (measured by an in vitro assay), or osmolality. In some embodiments, the polymorphs provided herein are stable for at least 1, 2, 3, or 4 weeks. For example, the polymorph does not show any change over at least 1, 2, 3, or 4 weeks in one or more of the following: polymorphic form (e.g., increase or decrease in a particular form), appearance, pH, impurity percentage, activity (measured by an in vitro assay), or osmolality. In some embodiments, the polymorphs provided herein are stable for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. For example, polymorphism is defined as showing no change in one or more of the following for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months: polymorphism (e.g., increase or decrease in a particular form), appearance, pH, percentage of impurities, activity (measured by in vitro assay), or osmolality. In the above, the phrase "show no change" means that the measured change for any parameter over the relevant period is less than 5% (e.g., less than 4%, less than 3%, less than 2%, less than 1%).

[0073] The present invention will now be described with reference to the following embodiments, which do not limit the invention in any way. All cited and referenced documents are incorporated by reference. [Examples]

[0074] (Example 1) Phase 1 preliminary dose setting trial This study was a single-center, open-label, parallel-group, randomized preliminary dose-finding study designed to evaluate the pharmacokinetic (PK), disease progression (PD), safety, and tolerability of repeated oral doses of linapra angulate (LG) at three dose levels in healthy men and women. Approximately 36 participants were randomized, with an estimated 12 evaluable participants per treatment group. The study design is shown in Figure 3.

[0075] Participants visited the clinic three times. Screening (Visit 1) was conducted from day -28 to day -1, and included eligibility confirmation and health status assessment. During Visit 2, participants were permitted to be admitted to the clinic on day -1 and remained there until day 4 for repeated dose administration of LG and evaluation of safety, PK, and PD. Participants fasted at least 8 hours before the expected dose time on day 1. Water was permitted as much as they liked, except 1 hour before and 30 minutes after administration, but other beverages were prohibited. On the morning of day 1, participants were randomized to one of three treatment groups. • LG50mgBID, 3 days (5 doses, final dose on the morning of the 3rd day) • LG100mg (2 x 50mg) BID, 3 days (5 doses, final dose on the morning of the 3rd day) • LG150mg (3 x 50mg) BID, 3 days (5 doses, final dose on the morning of the 3rd day)

[0076] Participants were carefully monitored by clinical staff during and after medication administration. Participants underwent 48-hour pH measurement assessments between days 2 and 4 of treatment. pH measurement assessments began before dose 3 (morning of day 2) and continued for 48 hours until 24 hours after the final dose. Vital signs and ECG were checked at regular intervals, and PK sampling was performed at selected times. The final end-of-study visit (visit 3) was conducted on day 7 (±2) or after early discontinuation. Each participant was expected to participate in the study for approximately 7 days, from the day of randomization (day 1, visit 2) to the end-of-study visit. Screening visits were conducted within 28 days prior to randomization (-28 to -1 day). The results of the pH measurement assessments are shown in Table 2 and Table 3 below.

[0077] [Table 2]

[0078] [Table 3]

[0079] In the treatment groups receiving 100 or 150 mg linapra angulate, administration of two daily doses (Day 2, BID) resulted in a median time of pH > 4 approximately 2 hours longer, or approximately 10% longer, compared to administration of one daily dose (Day 3, "QD"). Due to the small number of patients and wide variability in measurements, no clear conclusions could be drawn for the 50 mg treatment group.

[0080] (Example 2) Linaprazangurate dose determination (LEED) trial for erosive esophagitis Exam Overview This study included patients with erosive esophagitis (eGERD). Patients were divided into two cohorts: one with moderate to severe eGERD (LA grade C / D), and the other with milder eGERD (LA grade A / B) with a history of only partial response to PPI treatment. The primary endpoint of this study was to support dose selection of linapra angullate for a phase III program in eGERD by the primary evaluation of cure of erosive esophagitis after 4 weeks of treatment. The sample size, i.e., the number of patients required to measure dose-related efficacy, was based on the cohort of patients with moderate to severe eGERD. After initial endoscopic and other screening procedures, 248 patients were equally randomized to one of five treatment groups to receive either 4 weeks of treatment with linapra angullate at four dose levels, or 4 weeks of lansoprazole at an approved standard eGERD curative dose. Subsequently, an endoscopic evaluation of healing was performed, and healing was defined as the absence of esophageal erosions, i.e., the absence of erosive damage to the esophageal mucosa. Following the endoscopic evaluation, all patient groups received lansoprazole for 4 weeks in the maintenance phase. A retrospective primary review of endoscopic findings was performed, and 162 patients were available for evaluation of the primary endpoint. All 248 enrolled patients were included in the safety analysis.

[0081] method This multicenter trial (ClinicalTrials.gov identifier: NCT05055128) was conducted at 42 sites in Europe and the United States. The trial originated from the Declaration of Helsinki and was conducted in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) E6(R2), the EU Clinical Trials Directive, and protocols and ethical principles consistent with applicable local regulatory requirements. Patients provided written informed consent prior to participation in the trial.

[0082] Test design and treatment This study was a randomized, double-blind, controlled-action study with a parallel-group design, including four groups receiving linapra angulate and one group receiving lansoprazole. Pre-dose pharmacokinetic (PK) blood samples were taken in all patients immediately before the first and second doses on visit days 7, 14, and 28. After an 8-week standard treatment course with a PPI, 248 patients with erosive esophagitis due to GERD of grade C or D, and patients with erosive esophagitis due to GERD of grade A or B, who had at least a partial symptomatic response but were not yet endoscopically cured, were randomized.

[0083] Randomization to one of the following treatments—linapra langurate 25 mg, 50 mg, 75 mg, or 100 mg twice daily (BID), or lansoprazole 30 mg once daily (QD)—was based on a 1:1:1:1:1 scheme. Each center could not enroll more than approximately 20% of the total patient population (48 patients per center).

[0084] Each patient's participation in this study, including screening, blinded treatment, and open-label treatment periods, was approximately 60 days. Patients were randomized to a 4-week (28 days, -2 / +5 days) double-blind treatment and were provided with 35 days of IMP (including one additional blister pack dispensed on visit day 2 / 0) to allow treatment until the end of the visit period. All but 20 patients underwent endoscopic evaluation after the 4-week treatment. Following the endoscopic evaluation, all patients received a 4-week open-label treatment with lansoprazole 30 mg QD. Repeated symptom assessments were performed during this period to detect symptom patterns. The study design is shown in Figure 4.

[0085] Four doses of linapra angulate (25 mg, 50 mg, 75 mg, 100 mg, and placebo) were administered as tablets twice daily. The tablet formulations shown in Table 1 were used. The active control drug lansoprazole 30 mg and its placebo were administered once daily in the morning as capsules. The study drugs were taken with 100 mL of non-carbonated water at least 30 minutes before a meal. The duration of the double-blind treatment was 28 days - 2 / +5 days. For blinding treatment, each patient received two tablets (containing a dose of linapra angulate (LG) or its placebo) and one capsule (containing lansoprazole or its placebo) in the morning, and two tablets (containing a dose of linapra angulate (LG) or its placebo) in the evening, according to the scheme below.

[0086] [Table 4]

[0087] This study included six site visits and three telephone visits. Based on endoscopic findings and / or signed informed consent forms (ICF), a screening visit (Visit 1) was conducted within seven working days of randomization and the first dose administration (Visit 2). Subsequently, all patients visited the trial clinic / clinical trial site at 7 days (Visit 3), 14 days (Visit 4), 28 days (Visit 5), and at the end of the study / early termination visit (Visit 9). After Visit 5, there were three weekly telephone visits.

[0088] patient Inclusion Criteria • The patient must be male or female and between 18 and 75 years of age at the time informed consent was obtained. • Body Mass Index (BMI) at screening is ≥18 and ≤40 kg / m² 2 • Erosive esophagitis confirmed by endoscopy is the following type of erosive gastroesophageal reflux disease: ○ LA grade C or D (regardless of prior PPI treatment) ≤ 7 workdays prior to randomization or ○ LA Grade A or B within 7 working days of randomization and - A history of treatment with a PPI (all PPIs except lansoprazole) that followed a standard healing course at least 8 weeks prior to screening, and ≤7 working days of non-treatment during this period. and - At least a partial symptom response during at least 8 weeks of PPI treatment. • Willingness and ability to comply with all aspects of the protocol (including PK sampling, swallowing capsules, completing the diary, etc.)

[0089] The exclusion criteria included: • A history or presenting of clinically significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disease or disorder. Patients exhibiting so-called "warning features" in symptomatology, such as dysphagia, severe dysphagia, bleeding, weight loss, anemia, and bloody stools suggestive of possible malignant disease of the gastrointestinal (GI) tract. • Presents a clinically significant psychiatric diagnosis. • A history of malignant tumors in any organ system. • A history of esophageal ulcers, strictures, Barrett's esophagus, suspected esophagitis secondary to infection, inflammatory disease, or ingestion of corrosive chemicals, or any surgical or medical condition that may significantly alter the absorption, distribution, metabolism, or excretion of drugs or GERD. • A well-known severe atrophic gastritis. • Major surgeries scheduled during the examination period. • Clinically significant laboratory parameters outside the normal range that may suggest a new or poorly understood disease, may present an undue risk to patients, or may interfere with the evaluation of the study. Any of the following screening laboratory studies are excluded: ○In the main laboratory where the test is conducted, serum ALT or AST > 1.5 × upper limit of normal (ULN); ○In the main laboratory where the test is conducted, serum total bilirubin > 1.5 × ULN; ○In the main laboratory where the test is conducted, serum creatinine > 1.5 × ULN; ○Estimated glomerular filtration rate ≤ 59 mL / min (calculated using the formula for Modification of Diet in Renal Disease). • A history of positive test results for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), hepatitis B core antigen (anti-HBcAg), or hepatitis C virus (anti-HCV), or the presence of these findings at the time of screening. • After resting in a supine position for 10 minutes during screening, vital signs outside the following ranges: ○Systolic blood pressure (BP) > 160 mmHg or < 90 mmHg ○ Diastolic blood pressure > 100 mmHg or < 60 mmHg ○ Heart rate <40 beats or >95 beats per minute • History of QTc prolongation syndrome (e.g., QTc ≥ 450ms for men, ≥ 470ms for women). • Arrhythmia or clinically significant abnormality in a resting 12-lead ECG, as determined by the researcher during screening. • A history of severe allergies / hypersensitivity or a currently ongoing severe allergy / hypersensitivity. • Current or past use of alcohol, drug abuse, and / or anabolic steroids within two years prior to screening. • Pregnant or breastfeeding women.

[0090] evaluation The primary objective of this study was to support dose selection for linapra angulate by evaluating the resolution of erosive esophagitis due to GERD after 4 weeks of treatment. Resolution of erosive esophagitis due to GERD was based on endoscopic evaluation after 4 weeks of double-blind treatment.

[0091] A secondary objective of this study was the safety and tolerability of linapra angulate and lansoprazole at four dose levels, with lansoprazole serving as the active control agent. Another secondary objective of this study was the reflux-related symptom pattern during the first four weeks of treatment with four dose levels of linapra angulate and lansoprazole, as well as the symptom pattern during the subsequent additional four weeks (weeks 5–8) of open-label treatment with lansoprazole 30 mg QD. Based on the modified eDiary (mRESQ-eD), the number of 24 hours without heartburn and the number of 24 hours with at most mild heartburn symptoms were assessed, including splitting into daytime and nighttime assessments.

[0092] result healing The results show a clear dose-response in cure rates. In patients with moderate to severe eGERD (LA grade C / D), the highest mean LA grade improvement at 4 weeks was 2.1 in the lansoprazole group compared to 3.1 in the linapra angullate group (see Figure 5). LA grade improvement was higher in all LA grade C / D patients treated with linapra angullate than with lansoprazole. The highest 4-week cure rate was 38% in the lansoprazole group compared to 89% in the linapra angullate group; see Figure 6 (all LG dose groups) and Figure 7 (LG 75 mg dose group). The response in the linapra angullate 100 mg dose group was lower than expected, but this group included a higher proportion of the most severe ("difficult to treat") LA grade D patients than the other dose groups. Furthermore, in the LG100mg dose group, 6 out of 7 patients had a 4-week LA grade of A, meaning these patients failed to achieve a cure.

[0093] Although this study was not powerful enough to demonstrate a significant difference compared to the control drug lansoprazole, a post-hoc analysis showed that the cure rate for all LA grade C / D patients treated with linapra angulate was significantly higher than that of lansoprazole (Fisher's exact test, mean harmonic p-value = 0.0404).

[0094] In patients with milder eGERD (LA grade A / B), the highest 4-week cure rate was 81% in the lansoprazole group compared to 91% in the linapra angulate group.

[0095] The average cure rate was 69% in the lansoprazole treatment group, compared to 80% in all patients treated with linapra angulate (LA grade A / B / C / D); see Figure 8.

[0096] heartburn Reflux-related symptoms were assessed using the modified RESQ-eDiary (mRESQ-eD). Patients were asked to report every 12 hours, once before the morning dose of the investigational drug (IMP) and once before the evening dose. Results for all LA-grade erosions are shown in Table 4 (Table 5).

[0097] [Table 5]

[0098] Largest analysis population (FAS) Figure 9 shows a chart of the mRESQ-eD, which evaluates the number of heartburn-free 24-hour days over a week for all patients.

[0099] Double-blind period (weeks 1-4) Overall, the severity of heartburn in FAS was mild throughout the first week of treatment, with a maximum grade of 1.91 (minimum 0 = none; maximum 5 = severe). Patients receiving lansoprazole reported the highest severity grade of heartburn in both the morning and evening, while patients receiving LG 75 mg reported the lowest severity grade in both the morning and evening.

[0100] All linapran langurate treatment groups reported more heartburn-free days during weeks 1-4 compared to the lansoprazole treatment group. The LG 75mg treatment group reported the highest percentage of symptom-free days (29.2% in week 1, 52.9% in week 2, and 58.46.56% in week 3), but the LG 100mg treatment group reported the highest percentage in week 4 (62.2%).

[0101] Open-label period (weeks 5-8; all patients are treated with lansoprazole 30 mg QD) All linapran langurate treatment groups reported more heartburn-free days between weeks 5 and 8 compared to lansoprazole. At week 5, the LG 75 mg treatment group reported the highest percentage of heartburn-free days (69.6%). From weeks 6 to 8, the highest percentage of heartburn-free days was reported in the LG 25 mg treatment group (72.31.66% at week 6, 79.4% at week 7, and 82.4% at week 8).

[0102] FAS erosion Figure 10 shows the mRESQ-eD chart, which evaluates the number of heartburn-free 24-hour days over a week for all patients with LA grades A / B / C / D, and Figure 11 shows the corresponding chart for patients with LA grades C / D.

[0103] Double-blind period (weeks 1-4) Overall, the severity of heartburn in FAS was mild throughout the first week of treatment, with a maximum of 1.75 (minimum 0 = none; maximum 5 = severe). Patients receiving lansoprazole reported the highest heartburn severity in both the morning and evening, while patients receiving LG 75 mg reported the lowest heartburn severity in both the morning and evening.

[0104] All linapran langurate treatment groups reported more heartburn-free days during weeks 1-4 compared to the lansoprazole treatment group. The LG 75mg treatment group reported the highest percentage of symptom-free days during weeks 1-3 (33.3% in week 1, 57.2% in week 2, and 62.6% in week 3), but the LG 100mg treatment group reported the highest percentage in week 4 (65.2%).

[0105] In LA grade A / B, the highest percentage of heartburn-free days was reported in the LG 75mg treatment group during weeks 1-3, but in week 4, lansoprazole reported the most heartburn-free days.

[0106] In LA grade C / D, the highest percentage of heartburn-free days was observed in the treatment group with LG 50 mg in weeks 1 and 4, with LG 75 mg in week 2, and with LG 100 mg in week 3. The lansoprazole group reported the lowest percentage of heartburn-free days between weeks 2 and 4.

[0107] Open-label period (weeks 5-8; all patients are treated with lansoprazole 30 mg QD) All linapran langurate treatment groups reported more heartburn-free days between weeks 5 and 8 compared to the lansoprazole treatment group. At weeks 5 and 6, the LG 75 mg treatment group reported the highest percentage of heartburn-free days (72.6% and 73.0%, respectively), while at weeks 7 and 8, the LG 25 mg treatment group reported the highest percentage of heartburn-free days (81.9% and 87.6%, respectively).

[0108] In LA grade A / B, the highest percentage of heartburn-free days was reported with the LG75mg treatment group at week 5, with lansoprazole at week 6, and with the LG25mg treatment group at weeks 7 and 8.

[0109] In LA grade C / D, the highest percentage of heartburn-free days was reported with LG 50 mg at week 5 and with LG 75 mg at weeks 6-8. The lansoprazole group reported the lowest percentage of heartburn-free days at weeks 5-8.

[0110] safety Linapra angulate was generally well-tolerated, and safety data were comparable to those of lansoprazole. The number of adverse events was similar across the study groups, and no unexpected findings were observed. Across the entire study, 103 adverse events (AEs) were reported in 58 patients, and they were similarly distributed across different dose levels. No serious treatment-related AEs were reported. The most frequently reported treatment-related adverse event (TEAE) was COVID-19 infection, occurring in 4% of the total study population. See Table 5 (Table 6).

[0111] [Table 6]

Claims

1. Linapra angulate or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of gastrointestinal inflammatory disease or gastric acid-related disorders, which is administered orally to the subject once or twice daily in an amount of about 25 to about 100 mg.

2. Linapra angulate for use as specified in claim 1, wherein linapra angulate or a pharmaceutically acceptable salt thereof is administered in an amount of approximately 25 mg.

3. Linapra angulate for use as specified in claim 1, wherein linapra angulate or a pharmaceutically acceptable salt thereof is administered in an amount of approximately 50 mg.

4. Linapra angulate for use as specified in claim 1, wherein linapra angulate or a pharmaceutically acceptable salt thereof is administered in an amount of approximately 75 mg.

5. Linapra angulate for use as specified in claim 1, wherein linapra angulate or a pharmaceutically acceptable salt thereof is administered in an amount of approximately 100 mg.

6. Linapra angulate or a pharmaceutically acceptable salt thereof, administered once daily, for use as prescribed in any one of claims 1 to 5.

7. Linapra angulate or a pharmaceutically acceptable salt thereof, administered twice daily, for use as prescribed in any one of claims 1 to 5.

8. Linapra angulate for use as prescribed in any one of claims 1 to 7, wherein linapra angulate or a pharmaceutically acceptable salt thereof is administered for at least one week.

9. Linapra angulate for use as prescribed in any one of claims 1 to 8, wherein linapra angulate or a pharmaceutically acceptable salt thereof is administered for at least four weeks.

10. Linapra angulate for use as prescribed in any one of claims 1 to 9, wherein the gastrointestinal inflammatory or acid-related disorder is gastroesophageal reflux disease (GERD) or erosive gastroesophageal reflux disease (eGERD).

11. A linapral angle rate for use as defined in claim 10, wherein GERD or eGERD is LA grade A.

12. A linapral angle rate for use as defined in claim 10, wherein GERD or eGERD is LA grade B.

13. A linapral angle rate for use as defined in claim 10, wherein GERD or eGERD is LA grade C.

14. A linapral angle rate for use as defined in claim 10, wherein GERD or eGERD is LA grade D.

15. Linapra angulate for use as specified in any one of claims 1 to 14, wherein the subject exhibits improvement in the LA grade of reflux esophagitis after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof.

16. A linapral angle rate for use as defined in claim 15, wherein eGERD is LA grade A, and the improvement of LA grade is one step.

17. A linapral angle rate for use as defined in claim 15, wherein eGERD is LA grade B, and the improvement in LA grade is one or two levels.

18. A linapral angle rate for use as defined in claim 15, wherein eGERD is LA grade C, and the improvement in LA grade is 2 or 3 levels.

19. A linapral angle rate for use as defined in claim 15, wherein the eGERD is LA grade D, and the improvement in LA grade is 3 or 4 levels.

20. Linapra angulate for use as specified in any one of claims 1 to 19, wherein the subject exhibits an increase in the number of heartburn-free 24-hour days after oral administration of linapra angulate or a pharmaceutically acceptable salt thereof.

21. Linapra angullate for use as prescribed in any one of claims 1 to 19, wherein the subject has at least about 55%, at least about 60%, at least about 65%, at least about 70%, or at least about 75% of 24-hour days without heartburn over a one-week period after oral administration of linapra angullate or a pharmaceutically acceptable salt thereof.

22. Linapragrangurate or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of gastrointestinal inflammatory disease or gastric acid-related disease, wherein, after oral administration of linapragrangurate or a pharmaceutically acceptable salt thereof to a subject in an amount of about 25 to about 100 mg once or twice daily, the subject exhibits a minimum plasma concentration (Cmin) of linaprazan of at least 240 nmol / L.

23. Linapra angulate for use as specified in any one of claims 1 to 22, wherein linapra angulate exists as a crystalline salt of linapra angulate.

24. Linapra angulate for use as specified in claim 23, wherein linapra angulate exists as a crystalline hydrochloride of linapra angulate.

25. Linapra angulate for use as specified in claim 24, wherein the crystalline hydrochloride of linapra angulate is anhydrous.

26. Linapra angulate for use as defined in claim 25, wherein the anhydrous form of linapra angulate hydrochloride is Form 1.

27. Morphology 1 is a linapran angle for use as specified in claim 26, having an XRPD pattern with at least two peaks at °2θ values ​​selected from a list consisting of 9.1±0.2, 13.8±0.2, 14.0±0.2, 20.0±0.2, 22.9±0.2, 23.4±0.2, 24.4±0.2, 24.6±0.2, and 26.7±0.2, obtained using a CuKα1 line.

Images