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WO2024230943A1 - Linaprazan glurate pour le traitement du reflux gastro-œsophagien pathologique (gerd) - Google Patents

Linaprazan glurate pour le traitement du reflux gastro-œsophagien pathologique (gerd) Download PDF

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Publication number
WO2024230943A1
WO2024230943A1 PCT/EP2023/080637 EP2023080637W WO2024230943A1 WO 2024230943 A1 WO2024230943 A1 WO 2024230943A1 EP 2023080637 W EP2023080637 W EP 2023080637W WO 2024230943 A1 WO2024230943 A1 WO 2024230943A1
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Prior art keywords
linaprazan
glurate
grade
pharmaceutically acceptable
acceptable salt
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Kjell Andersson
Peter Unge
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Cinclus Pharma Holding Publ AB
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Cinclus Pharma Holding Publ AB
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Priority to MX2025013362A priority Critical patent/MX2025013362A/es
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the invention relates to linaprazan glurate, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a gastrointestinal inflammatory or a gastric acid related disease, such as (erosive) gastroesophageal reflux disease.
  • the treatment involves oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, to a patient in an amount of from about 25 to about 100 mg once or twice daily.
  • Gastroesophageal reflux disease is a digestive disease that affects the lower esophageal sphincter (the ring of muscle between the esophagus and stomach), which causes retrograde flow of gastric content into the esophagus.
  • Symptoms of GERD include dental corrosion, dysphagia, heartburn, acid regurgitation, non-cardiac chest pain, extraesophageal symptoms such as chronic cough, hoarseness, reflux-induced laryngitis and asthma.
  • GERD When left untreated, GERD may result in complications such as esophagitis (inflammation of the esophagus), esophageal stricture, Barrett's esophagus (a condition involving an abnormal (metaplastic) change in the mucosal cells lining the lower portion of the esophagus), dysplasia and cancer (e.g., MALToma or adenocarcinoma).
  • Linaprazan glurate (5- ⁇ 2-[( ⁇ 8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[l,2-a]pyridine-6- yl ⁇ carbonyl)-amino]ethoxy ⁇ -5-oxopentanoic acid; previously known as X842) is a potassiumcompetitive acid blocker (P-CAB), which is another class of drugs under development for treatment of GERD.
  • P-CABs competitively inhibit the gastric hydrogen potassium pump (H+/K+ ATPase) in the parietal cells and have a considerably faster onset to maximum effect than PPIs (typically 1-2 hours vs. 3-5 days).
  • Neutral intragastric pH has been demonstrated two hours after the first dose with linaprazan glurate in healthy subjects. With a plasma half-life of approximately 10 hours, it is expected that administration of linaprazan glurate once or twice daily may provide 24h acid control.
  • FIG. 1 is a plot of the healing rate (%) after 4 weeks vs. the mean percentage of time (in 24 hour) with intragastric pH>4 (based on Yuan et al., Gastroenterol. 2007, vol. 132(4), suppl. 2, A-489, No T1202).
  • FIG. 2 is a plot of the intragastric pH-level vs. the plasma concentration of linaprazan (nmol/L). At plasma concentrations above 240 nmol/L (the striped area), the intragastric pH is almost always above 4.
  • FIG. 3 provides a schematic diagram of the study design for the Linaprazan glurate Phase 1 exploratory dose-finding study.
  • FIG. 4 provides a schematic diagram of the study design for the Linaprazan glurate Erosive Esophagitis Dose ranging (LEED) study.
  • FIG. 5 is a plot of the mean LA grade improvement for LA grade C/D patients after 4 weeks of treatment with different doses of linaprazan glurate (LG) or with 30 mg QD lansoprazole (LAN).
  • FIG. 6 is a plot of the healing rate (%) for LA grade C/D patients after 4 weeks of treatment with different doses of linaprazan glurate (LG) or with 30 mg QD lansoprazole (LAN).
  • FIG. 7 is a plot of the healing rate (%) for LA grade C/D patients after 4 weeks of treatment with 75 mg BID linaprazan glurate (LG) or with 30 mg QD lansoprazole (LAN).
  • FIG. 8 is a plot of the healing rate (%) for all LA grade A/B/C/D patients after 4 weeks of treatment with different doses of linaprazan glurate (LG) or with 30 mg QD lansoprazole (LAN).
  • FIG. 9 is a chart of the mRESQ-eD assessed heartburn-free 24-hour days over a week for all patients during 8 weeks of treatment with different doses of linaprazan glurate (LG) or with 30 mg QD lansoprazole (LAN).
  • FIG. 10 is a chart of the mRESQ-eD assessed heartburn-free 24-hour days over a week for all LA grade A/B/C/D patients during 8 weeks of treatment with different doses of linaprazan glurate (LG) or with 30 mg QD lansoprazole (LAN).
  • LG linaprazan glurate
  • LAN 30 mg QD lansoprazole
  • FIG. 11 is a chart of the mRESQ-eD assessed heartburn-free 24-hour days over a week for all LA grade C/D patients during 8 weeks of treatment with different doses of linaprazan glurate (LG) or with 30 mg QD lansoprazole (LAN).
  • LG linaprazan glurate
  • LAN 30 mg QD lansoprazole
  • FIG. 12 shows the X-ray powder diffractogram of Form 1 of the HCI salt of linaprazan glurate, as obtained from a slurry in DMF.
  • FIG. 13 shows the differential scanning calorimetry (DSC) thermogram of Form 1 of the HCI salt of linaprazan glurate, as crystallized from DMF using EtOAc as the anti-solvent.
  • FIG. 14 shows the dynamic vapour sorption (DVS) weight change plot (A) and the DVS isotherm plot (B) for Form 1 of the HCI salt of linaprazan glurate, as crystallized from DMF using EtOAc as the antisolvent.
  • DVS dynamic vapour sorption
  • the invention relates to linaprazan glurate, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a gastrointestinal inflammatory or a gastric acid related disease, wherein linaprazan glurate, or a pharmaceutically acceptable salt thereof, is orally administered to a subject in an amount of from about 25 to about 100 mg once or twice daily.
  • linaprazan glurate, or a pharmaceutically acceptable salt thereof is administered once daily (QD). In some embodiments, linaprazan glurate, or a pharmaceutically acceptable salt thereof, is administered twice daily (BID). It has been found that administration of linaprazan glurate twice daily results in approximately 10% longer time per day (about 2 hours) with gastric pH>4 than administration of linaprazan glurate once daily. It has previously been reported that 24-hour median pH and % of time pH >4 in 24 hour are good predictors for erosive esophagitis healing at 8 weeks, and that the better the acid suppression (pH>4), the better the efficacy in healing esophagitis (Hunt, Aliment. Pharmacol. Ther.
  • FIG. 1 A plot of the healing rate (%) after 4 weeks vs. mean percentage of time with intragastric pH>4 is shown in Figure 1.
  • Administration of linaprazan glurate twice daily may therefore provide better results in the treatment of gastrointestinal inflammatory or gastric acid related diseases than administration of linaprazan glurate once daily.
  • linaprazan glurate is quickly metabolized into linaprazan, which is the active metabolite.
  • the plasma concentration of linaprazan glurate is only very low and difficult to determine, but the plasma concentration of linaprazan may be determined instead.
  • the invention relates to linaprazan glurate, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a gastrointestinal inflammatory or a gastric acid related disease, wherein following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, to a subject in an amount of from 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.
  • Cmin minimum plasma concentration
  • linaprazan glurate, or a pharmaceutically acceptable salt thereof is administered once or twice daily in an amount of from about 25 to about 100 mg, such as from about 25 to about 75 mg, such as from about 25 to about 50 mg, such as from about 50 to about 100 mg, such as from about 50 to about 75 mg, or such as from about 75 to about 100 mg.
  • linaprazan glurate, or a pharmaceutically acceptable salt thereof is administered in an amount of about 25 mg once daily.
  • linaprazan glurate, or a pharmaceutically acceptable salt thereof is administered in an amount of about 25 mg twice daily.
  • linaprazan glurate, or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 mg once daily. In some embodiments, linaprazan glurate, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50 mg twice daily. In some embodiments, linaprazan glurate, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 75 mg once daily. In some embodiments, linaprazan glurate, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 75 mg twice daily. In some embodiments, linaprazan glurate, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100 mg once daily. In some embodiments, linaprazan glurate, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100 mg twice daily.
  • linaprazan glurate or a pharmaceutically acceptable salt thereof, is administered at least 30 minutes prior to meals.
  • linaprazan glurate, or a pharmaceutically acceptable salt thereof is administered on demand. In some embodiments, linaprazan glurate, or a pharmaceutically acceptable salt thereof, is administered for at least 1 week. In some embodiments, linaprazan glurate, or a pharmaceutically acceptable salt thereof, is administered for at least 2 weeks. In some embodiments, linaprazan glurate, or a pharmaceutically acceptable salt thereof, is administered for at least 3 weeks. In some embodiments, linaprazan glurate, or a pharmaceutically acceptable salt thereof, is administered for at least 4 weeks. In some embodiments, linaprazan glurate, or a pharmaceutically acceptable salt thereof, is administered for at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks or at least 10 weeks.
  • linaprazan glurate or a pharmaceutically acceptable salt thereof, is administered in an amount of from about 25 to about 100 mg twice daily for 4 weeks.
  • the gastrointestinal inflammatory or gastric acid related disease is gastritis, gastroesophageal reflux disease (GERD), erosive gastroesophageal reflux disease (eGERD), H. pylori infection, Zollinger-Ellison syndrome, peptic ulcer disease (including gastric ulcers and duodenal ulcers), bleeding gastric ulcer, symptoms of gastroesophageal reflux disease (including heartburn, regurgitation and nausea), gastrinoma, acute upper gastrointestinal bleeding, or damage or bleeding caused by aspirin or NSAIDs.
  • the gastrointestinal inflammatory or gastric acid related disease is gastroesophageal reflux disease (GERD).
  • the gastrointestinal inflammatory or gastric acid related disease is erosive gastroesophageal reflux disease (eGERD).
  • eGERD erosive gastroesophageal reflux disease
  • the severity of esophagitis is typically indicated using the Los Angeles (LA) classification of reflux esophagitis, which is based on an endoscopic assessment of the patient.
  • LA grade scoring system divides reflux esophagitis into four categories (LA grade A to D) based on the extent of esophageal mucosal breaks.
  • the mildest form, LA grade A esophagitis is defined as one or more mucosal breaks not longer than 5 mm, that do not extend between the tops of two mucosal folds.
  • LA grade B esophagitis is defined as one or more mucosal breaks longer than 5 mm that do not extend between the tops of two mucosal folds.
  • LA grade C esophagitis is defined as one or more mucosal breaks that are continuous between the tops of two mucosal folds, but which involves less than 75% of the esophageal circumference.
  • the most severe form, LA grade D esophagitis is defined as one or more mucosal breaks involving at least 75% of the esophageal circumference (Lundell et aL, Gut 1999, vol. 45, p. 172-180).
  • the GERD or eGERD is LA grade A. In some embodiments, the GERD or eGERD is LA grade B. In some embodiments, the GERD or eGERD is LA grade C. In some embodiments, the GERD or eGERD is LA grade D.
  • the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, an improvement of the LA grade of reflux esophagitis.
  • improved of the LA grade and “LA grade improvement” refer to one or more steps from one LA grade to a lower LA grade (such as from grade D to grade C, B or A) or to being healed.
  • the improvement of the LA grade is 1 step.
  • the improvement of the LA grade is 2 steps.
  • the improvement of the LA grade is 3 steps.
  • the improvement of the LA grade is 4 steps.
  • 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 following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of from about 25 to about 100 mg twice daily for at least 1, 2, 3 or 4 weeks.
  • the subject is healed following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, for at least 1, 2, 3 or 4 weeks. In some embodiments, the subject is healed following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of from about 25 to about 100 mg twice daily for 4 weeks.
  • the GERD or eGERD is LA grade A, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of from about 25 to about 100 mg once or twice daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1 step.
  • the GERD or eGERD is LA grade A, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 25 mg once daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1 step.
  • the GERD or eGERD is LA grade A, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 25 mg twice daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1 step.
  • the GERD or eGERD is LA grade A, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 50 mg once daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1 step.
  • the GERD or eGERD is LA grade A, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 50 mg twice daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1 step.
  • the GERD or eGERD is LA grade A, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 75 mg once daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1 step.
  • the GERD or eGERD is LA grade A, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 75 mg twice daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1 step.
  • the GERD or eGERD is LA grade A, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 100 mg once daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1 step.
  • the GERD or eGERD is LA grade A, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 100 mg twice daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1 step.
  • An LA grade A subject exhibiting an LA grade improvement of 1 step is considered healed.
  • the GERD or eGERD is LA grade B, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of from about 25 to about 100 mg once or twice daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1 or 2 steps, more preferably 2 steps.
  • the GERD or eGERD is LA grade B, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 25 mg once daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1 or 2 steps, more preferably 2 steps.
  • the GERD or eGERD is LA grade B, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 25 mg twice daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1 or 2 steps, more preferably 2 steps.
  • the GERD or eGERD is LA grade B, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 50 mg once daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1 or 2 steps, more preferably 2 steps.
  • the GERD or eGERD is LA grade B, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 50 mg twice daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1 or 2 steps, more preferably 2 steps.
  • the GERD or eGERD is LA grade B, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 75 mg once daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1 or 2 steps, more preferably 2 steps.
  • the GERD or eGERD is LA grade B, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 75 mg twice daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1 or 2 steps, more preferably 2 steps.
  • the GERD or eGERD is LA grade B, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 100 mg once daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1 or 2 steps, more preferably 2 steps.
  • the GERD or eGERD is LA grade B, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 100 mg twice daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1 or 2 steps, more preferably 2 steps.
  • An LA grade B subject exhibiting an LA grade improvement of 2 steps is considered healed.
  • the GERD or eGERD is LA grade C, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of from about 25 to about 100 mg once or twice daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1, 2 or 3 steps, more preferably 2 or 3 steps, and most preferably 3 steps.
  • the GERD or eGERD is LA grade C, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 25 mg once daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1, 2 or 3 steps, more preferably 2 or 3 steps, and most preferably 3 steps.
  • the GERD or eGERD is LA grade C, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 25 mg twice daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1, 2 or 3 steps, more preferably 2 or 3 steps, and most preferably 3 steps.
  • the GERD or eGERD is LA grade C, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 50 mg once daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1, 2 or 3 steps, more preferably 2 or 3 steps, and most preferably 3 steps.
  • the GERD or eGERD is LA grade C, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 50 mg twice daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1, 2 or 3 steps, more preferably 2 or 3 steps, and most preferably 3 steps.
  • the GERD or eGERD is LA grade C, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 75 mg once daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1, 2 or 3 steps, more preferably 2 or 3 steps, and most preferably 3 steps.
  • the GERD or eGERD is LA grade C, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 75 mg twice daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1, 2 or 3 steps, more preferably 2 or 3 steps, and most preferably 3 steps.
  • the GERD or eGERD is LA grade C, and the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 100 mg once daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1, 2 or 3 steps, more preferably 2 or 3 steps, and most preferably 3 steps.
  • the GERD or eGERD is LA grade C
  • the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 100 mg twice daily for at least 1, 2, 3 or 4 weeks, an LA grade improvement of 1, 2 or 3 steps, more preferably 2 or 3 steps, and most preferably 3 steps.
  • An LA grade C subject exhibiting an LA grade improvement of 3 steps is considered healed.
  • the GERD or eGERD is LA grade D
  • the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of from about 25 to about 100 mg once or twice daily for at least 1, 2, 3 or 4 weeks, 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, and most preferably 4 steps.
  • the GERD or eGERD is LA grade D
  • the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 25 mg once daily for at least 1, 2, 3 or 4 weeks, 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, and most preferably 4 steps.
  • the GERD or eGERD is LA grade D
  • the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 25 mg twice daily for at least 1, 2, 3 or 4 weeks, 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, and most preferably 4 steps.
  • the GERD or eGERD is LA grade D
  • the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 50 mg once daily for at least 1, 2, 3 or 4 weeks, 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, and most preferably 4 steps.
  • the GERD or eGERD is LA grade D
  • the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 50 mg twice daily for at least 1, 2, 3 or 4 weeks, 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, and most preferably 4 steps.
  • the GERD or eGERD is LA grade D
  • the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 75 mg once daily for at least 1, 2, 3 or 4 weeks, 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, and most preferably 4 steps.
  • the GERD or eGERD is LA grade D
  • the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 75 mg twice daily for at least 1, 2, 3 or 4 weeks, 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, and most preferably 4 steps.
  • the GERD or eGERD is LA grade D
  • the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 100 mg once daily for at least 1, 2, 3 or 4 weeks, 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, and most preferably 4 steps.
  • the GERD or eGERD is LA grade D
  • the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of about 100 mg twice daily for at least 1, 2, 3 or 4 weeks, 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, and most preferably 4 steps.
  • An LA grade D subject exhibiting an LA grade improvement of 4 steps is considered healed.
  • the subject exhibits, following oral administration of linaprazan glurate, or a pharmaceutically acceptable salt thereof, a relief of reflux-related symptoms.
  • the subject exhibits an increase in 24-hour days with at most mild symptoms.
  • the subject exhibits an increase in heartburn-free 24-hour days.
  • Relief of reflux-related symptoms may be assessed based on the modified Reflux Symptom Reflux Questionnaire-electronic Diary (mRESQ-eDiary), which is an electronic symptom diary developed for use in partial responders to proton pump inhibitors.
  • mRESQ-eDiary modified Reflux Symptom Reflux Questionnaire-electronic Diary
  • mRESQ-eD has three domains (i.e., heartburn, other GERD signs/symptoms and regurgitations/reflux) and eight items (Andrae et al., Clin. Transl. Gastroenterol. 2020, 11(1): e00117).
  • the subject has at least about 55% heartburn-free 24-hour days over a week, such as 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% heartburn-free 24-hour days over a week. In some embodiments, the subject has at least about 95% heartburn-free 24-hour days over a week.
  • Also provided herein is a method for treating or preventing a gastrointestinal inflammatory or a gastric acid related disease in a subject in need thereof, the method comprising orally administering to the subject linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of from about 25 to about 100 mg once or twice daily. Also provided herein is the use of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a gastrointestinal inflammatory or a gastric acid related disease, wherein linaprazan glurate, or a pharmaceutically acceptable salt thereof, is administered orally in an amount of from about 25 to about 100 mg once or twice daily.
  • the invention relates to a pharmaceutical formulation comprising linaprazan glurate, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a gastrointestinal inflammatory or a gastric acid related disease, wherein the pharmaceutical formulation comprises linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of from about 25 to about 100 mg and is orally administered to a subject once or twice daily.
  • Formulations comprising linaprazan glurate, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a gastrointestinal inflammatory or a gastric acid related disease, wherein the pharmaceutical formulation comprises linaprazan glurate, or a pharmaceutically acceptable salt thereof, in an amount of from about 25 to about 100 mg and is orally administered to a subject once or twice daily.
  • Linaprazan glurate may be administered to the subject as a formulation in the form of e.g., a tablet or capsule.
  • a formulation of linaprazan glurate, or a pharmaceutically acceptable salt thereof comprises a therapeutically effective amount linaprazan glurate, or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable excipients.
  • the excipients may e.g., include fillers, binders, surfactants, disintegrants, glidants and lubricants.
  • the formulation comprises a surfactant.
  • the surfactant may be a cationic surfactant, an anionic surfactant or a nonionic surfactant.
  • cationic surfactants include, but are not limited to, cetyltrimethylammonium bromide (cetrimonium bromide) and cetylpyridinium chloride.
  • anionic surfactants include, but are not limited to, sodium dodecyl sulfate (sodium lauryl sulfate) and ammonium dodecyl sulfate (ammonium lauryl sulfate).
  • nonionic surfactants include, but are not limited to, glycerol monooleate, glycerol monostearate, polyoxyl castor oil (Cremophor EL), poloxamers (e.g., poloxamer 407 or 188), polysorbate 80 and sorbitan esters (Tween).
  • the surfactant is an anionic surfactant.
  • the anionic surfactant is sodium dodecyl sulfate.
  • the surfactant may be present in the formulation in an amount of from about 1.0% (w/w) relative to the amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof, such as from about 2.0 to about 12.0% (w/w), such as from about 4.0 to about 12.0% (w/w), such as from about 6.0 to about 12.0% (w/w), such as from about 8.0 to about 12.0% (w/w), or such as from about 10.0 to about 12.0% (w/w) relative to the amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof.
  • the amount of surfactant in the formulation is preferably as low as possible.
  • the formulation comprises from about 1.0 to about 11.0% (w/w), such as from about 1.0 to about 10.0% (w/w), such as from about 1.0 to about 9.0% (w/w), such as from about 1.0 to about 8.0% (w/w), or such as from about 1.0 to about 7.0% (w/w) of surfactant relative to the amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof.
  • the formulation comprises from about 2.0 to about 11.0% (w/w), such as from about 2.0 to about 10.0% (w/w), such as from about 2.0 to about 9.0% (w/w), such as from about 2.0 to about 8.0% (w/w), or such as from about 2.0 to about 7.0% (w/w) of surfactant relative to the amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof.
  • the formulation comprises from about 4.0 to about 11.0% (w/w), such as from about 4.0 to about 10.0% (w/w), such as from about 4.0 to about 9.0% (w/w), such as from about 4.0 to about 8.0% (w/w), or such as from about 4.0 to about 7.0% (w/w) of surfactant relative to the amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof.
  • the formulation comprises surfactant in an amount of about 11.0% (w/w) or less, relative to the amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises surfactant in an amount of about 10.0% (w/w) or less, relative to the amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises surfactant in an amount of about 9.0% (w/w) or less, relative to the amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises surfactant in an amount of about 8.0% (w/w) or less, surfactant relative to the amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof.
  • the formulation comprises a filler.
  • suitable fillers include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose (such as lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, dry starch, hydrolyzed starches and pregelatinized starch.
  • the filler is lactose, such as lactose monohydrate.
  • the formulation comprises a binder.
  • suitable binders include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (such as sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums (such as acacia gum and tragacanth gum), sodium alginate, cellulose derivatives (such as hydroxypropylmethylcellulose (or hypromellose), hydroxypropylcellulose and ethylcellulose) and synthetic polymers (such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid copolymers and polyvinylpyrrolidone (povidone)).
  • sugars such as sucrose, glucose, dextrose, lactose and sorbitol
  • polyethylene glycol such as
  • the formulation comprises a disintegrant.
  • suitable disintegrants include, but are not limited to, dry starch, modified starch (such as (partially) pregelatinized starch, sodium starch glycolate and sodium carboxymethyl starch), alginic acid, cellulose derivatives (such as sodium carboxymethylcellulose, hydroxypropyl cellulose, and low substituted hydroxypropyl cellulose (L-HPC)) and cross-linked polymers (such as carmellose, croscarmellose sodium, carmellose calcium and cross-linked PVP (crospovidone)).
  • the disintegrant is croscarmellose sodium.
  • the formulation comprises a glidant or lubricant.
  • suitable glidants 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 granulated silicon oxide, starch, sodium lauryl sulfate, boric acid, magnesium oxide, waxes (such as carnauba wax), hydrogenated oil, polyethylene glycol, sodium benzoate, polyethylene glycol, and mineral oil.
  • the glidant is colloidal anhydrous silica.
  • a tablet formulation of linaprazan glurate has the composition as shown in table 1:
  • formulations may be prepared in a conventional manner using conventional excipients.
  • the ingredients of the formulation are mixed to a homogenous mixture and then formulated as tablets or capsules.
  • the homogenous mixture of the ingredients may be compressed into tablets using conventional techniques, such as a rotary tablet press.
  • the mixture of ingredients may also be granulated.
  • the mixture of ingredients may be wetted by the addition of a liquid, such as water and/or an appropriate organic solvent (e.g., ethanol or isopropanol), and thereafter granulated and dried.
  • granules may be prepared by dry granulation, such as by roller compaction. The granules obtained may be compressed into tablets using conventional techniques.
  • Capsules may comprise a powder mixture or small multiparticulates (such as granules, extruded pellets or minitablets) of the ingredients. If desirable, any of the tablets, capsules, granules, extruded pellets and minitablets mentioned above may be coated with one or more coating layers. Such coating layers may be applied by methods known in the art, such as by film coating involving perforated pans and fluidized beds. In some embodiments, the formulation is in the form of a tablet.
  • linaprazan glurate is present in crystalline form.
  • linaprazan glurate is present as a crystalline anhydrate, such as disclosed in US 2022/0002297.
  • the crystalline anhydrate of linaprazan glurate is Form A.
  • Form A has an X-ray powder diffraction (XRPD) pattern, obtained with CuKal-radiation, with at least peaks at °20 values of 9.9 ⁇ 0.2 and 11.5 ⁇ 0.2.
  • XRPD X-ray powder diffraction
  • Form A has an X-ray powder diffraction pattern, obtained with CuKal-radiation, with 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.
  • Form A has an XRPD pattern, obtained with CuKal-radiation, with at least peaks at °20 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.
  • Form A has an XRPD pattern, obtained with CuKal-radiation, with at least peaks at °20 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, and one or more of 18.2 ⁇ 0.2, 18.4 ⁇ 0.2, 21.0 ⁇ 0.2, 21.2 ⁇ 0.2 and 23.3 ⁇ 0.2.
  • linaprazan glurate is present as a pharmaceutically acceptable salt of linaprazan glurate.
  • suitable examples of pharmaceutically acceptable salts of linaprazan glurate include, but are not limited to, a hydrochloride salt, a hydrobromide salt, a methanesulfonic acid salt ("mesylate") or a maleic acid salt ("maleate").
  • linaprazan glurate is present as a hydrochloride salt of linaprazan glurate.
  • linaprazan glurate is present as a crystalline hydrochloride salt of linaprazan glurate, such as disclosed in WO 2023/079094.
  • linaprazan glurate is present as a crystalline HCI salt of linaprazan glurate, which is stable at a relative humidity (RH) of 94% at room temperature.
  • RH relative humidity
  • Such crystalline HCI salts can be 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.
  • linaprazan glurate is present as a crystalline anhydrate of the HCI salt of linaprazan glurate.
  • the crystalline anhydrate of the HCI salt of linaprazan glurate is Form 1. This stable form may be prepared directly from the free base of linaprazan glurate, or by certain crystallisation techniques using the hydrochloride salt thereof, e.g. from a slurry in DMF, pyridine, benzyl alcohol or ethanol; by anti-solvent crystallisation from DMF or pyridine and certain anti-solvents; or by cooling from DMF or pyridine.
  • Form 1 of the HCI salt of linaprazan glurate has an X-ray powder diffraction (XRPD) pattern, obtained with CuKal-radiation, with at least two peaks at °20 values selected from the 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.
  • XRPD X-ray powder diffraction
  • Form 1 of the HCI salt of linaprazan glurate has an XRPD pattern, obtained with CuKal-radiation, with at least peaks at °20 values of 20.0 ⁇ 0.2 and 26.7 ⁇ 0.2.
  • Form 1 of the HCI salt of linaprazan glurate has an XRPD pattern, obtained with CuKal-radiation, with at least four peaks at °20 values selected from the 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.
  • Form 1 of the HCI salt of linaprazan glurate has an XRPD pattern, obtained with CuKal-radiation, with at least peaks at °20 values of 20.0 ⁇ 0.2, 24.4 ⁇ 0.2, 24.6 ⁇ 0.2 and 26.7 ⁇ 0.2.
  • Form 1 of the HCI salt of linaprazan glurate has an XRPD pattern, obtained with CuKal-radiation, with at least peaks at °20 values of 20.0 ⁇ 0.2, 24.4 ⁇ 0.2, 24.6 ⁇ 0.2 and 26.7 ⁇ 0.2, and or more of 9.1 ⁇ 0.2, 13.8 ⁇ 0.2, 14.0 ⁇ 0.2, 22.9 ⁇ 0.2 and 23.4 ⁇ 0.2.
  • Form 1 of the HCI salt of linaprazan glurate has an XRPD pattern, obtained with CuKal-radiation, with at least peaks at °20 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.
  • Form 1 of the HCI salt of linaprazan glurate has an XRPD pattern, obtained with CuKal-radiation, with at least peaks at °20 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.
  • Form 1 of the HCI salt of linaprazan glurate has an XRPD pattern, obtained with CuKal-radiation, with at least peaks at °20 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, and one or more of 16.2 ⁇ 0.2, 18.6 ⁇ 0.2, 22.2+0.2, 25.6+0.2 and 27.9 ⁇ 0.2.
  • Form 1 of the HCI salt of linaprazan glurate has an XRPD pattern, obtained with CuKal-radiation, substantially as shown in Figure 12.
  • Form 1 of the HCI salt of linaprazan glurate has a DSC curve comprising an endotherm between about 230 °C and about 240 °C.
  • Form 1 of the HCI salt of linaprazan glurate has a DSC curve comprising an endotherm at approximately 233 °C.
  • the DSC thermogram of Form 1 of the HCI salt of linaprazan glurate is shown in Figurel3.
  • an “effective amount” or “therapeutically effective amount” refer to a sufficient amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof, that, following administration to a subject, will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic use is the amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof, required to provide a clinically significant decrease in disease symptoms.
  • An appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • the terms “subject,” “individual,” or “patient,” used interchangeably, refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are suitable for human pharmaceutical use and that are generally safe, non-toxic and neither biologically nor otherwise undesirable.
  • the terms “twice daily” or “BID” (bis in die) refer to administration of a drug at two different times during the day, such as separated by at least about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours.
  • twice daily refers to once in the morning and once in the evening.
  • Administration of two or more unit doses (e.g., pills, tablets or capsules) of a drug at a single time during the day is considered once daily administration, whereas administration of two or more unit doses (e.g., pills, tablets or capsules) of a drug at two different times during the day is considered twice daily administration.
  • the term "about” refers to a value or parameter herein that includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to "about 20” includes description of "20". Numeric ranges are inclusive of the numbers defining the range. Generally speaking, the term “about” refers to the indicated value of the variable and to all values of the variable that are within the experimental error of the indicated value (e.g., within the 95% confidence interval for the mean) or within 10 percent of the indicated value, whichever is greater.
  • crystalline form or “polymorph” refer to crystals of the same molecule that have different physical properties as a result of the order of the molecules in the crystal lattice.
  • Polymorphs of a single compound have one or more different chemical, physical, mechanical, electrical, thermodynamic, and/or biological properties from each other. Differences in physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility, density (important in composition and product manufacturing), dissolution rates (an important factor in determining bioavailability), solubility, melting point, chemical stability, physical stability, powder flowability, water sorption, compaction, and particle morphology. Differences in stability can result from changes in chemical reactivity (e.g.
  • a dosage form discolours more rapidly when comprised of one polymorph than when comprised of another polymorph
  • mechanical changes e.g., crystal changes on storage as a kinetically favoured polymorph converts to a thermodynamically more stable polymorph
  • one polymorph is more hygroscopic than the other.
  • sol u bil ity/d issol u tion differences some transitions affect potency and/or toxicity.
  • the physical properties of the crystal may be important in processing; for example, one polymorph might be more likely to form solvates or might be difficult to filter and wash free of impurities (i.e., particle shape and size distribution might be different between one polymorph relative to the other).
  • Polymorph does not include amorphous forms of the compound.
  • anhydrate or “anhydrous form” refers to a crystalline form of linaprazan glurate, or a pharmaceutically acceptable salt thereof, that has 0.5% or less by weight water, for example 0.4% or less, or 0.3% or less, or 0.2% or less, or 0.1% or less by weight water.
  • the term “stable” means that the crystalline forms (i.e., polymorphs) do not exhibit a change in one or more of polymorph form (e.g., an increase or decrease of a certain form), appearance, pH, percent impurities, activity (as measured by in vitro assays), or osmolarity over time.
  • the polymorphs provided herein are stable for at least 1, 2, 3 or 4 weeks.
  • the polymorphs do not exhibit a change in one or more of polymorph form (e.g., an increase or decrease of a certain form), appearance, pH, percent impurities, activity (as measured by in vitro assays), or osmolarity over at least 1, 2, 3 or 4 weeks.
  • the polymorphs provided herein are stable for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months.
  • the polymorphs do not exhibit a change in one or more of polymorph form (e.g., an increase or decrease of a certain form), appearance, pH, percent impurities, activity (as measured by in vitro assays), or osmolarity over at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months.
  • the phrase "do not exhibit a change” refers to a change of less than 5% (e.g., less than 4%, less than 3%, less than 2%, less than 1%) as measured for any of the parameters over the relevant time period.
  • the study was a single-centre, open-label, parallel-group, randomised exploratory dose-finding study designed to evaluate the PK, PD, safety and tolerability of repeated oral doses of linaprazan glurate (LG) at 3 dose levels, in healthy male and female subjects. About 36 subjects were randomised for an estimated total of 12 evaluable subjects per treatment arm. The study design is shown in Figure 3.
  • Subjects came to the clinic for 3 visits.
  • the screening (Visit 1) took place from Day -28 to Day -1 and included an eligibility check and review of health status.
  • Visit 2 subjects were admitted to the clinic on Day -1 and remained at the clinic until Day 4 for repeated dose of LG administration and safety, PK and PD assessments.
  • the subjects fasted for at least 8 hours before the anticipated dosing time on Day 1. Water, but no other drinks, was allowed as desired except for 1 hour before and 30 minutes after dosing.
  • subjects were randomised to one of 3 treatment arms:
  • Subjects were carefully monitored by clinical staff during and after dosing. Subjects had a 48-hour pH-metry assessment during Day 2-4 of treatment. The pH-metry assessment was started prior to Dose 3 (in the morning of Day 2) and continued for 48 hours, until 24 hours post last dose. Vital signs and ECG were checked at regular intervals and PK sampling was done at selected timepoints. A final end-of-study visit (Visit 3) took place on Day 7 ( ⁇ 2) or after early withdrawal. Each subject was expected to participate in the study for approximately 7 days from the day of randomisation (Day 1, Visit 2) to the End-of Study Visit. The Screening Visit was performed within 28 days prior to randomisation (Day -28 to Day -1). The results of the pH-metry assessment are shown in tables 2 and 3 below.
  • the sample size, i.e., the number of patients needed, for measuring dose related efficacy was based on the patient cohort with moderate to severe eGERD.
  • the study was a randomized, double-blind, active comparator-controlled study with a parallel group design including four arms with linaprazan glurate and one arm with lansoprazole.
  • Pharmacokinetic (PK) blood sampling pre-dose close before the first and the second dose administration was performed at Day 7, Day 14 and Day 28 visits days in all patients.
  • One site could not enroll more than about 20% of the overall number of patients (48 patients per site).
  • the patients were randomized for 4 weeks (28 days, -2/+5 days) of double-blind treatment and were provided with IMP for 35 days (including one additional blister pack dispensed at Visit 2/Day 0) to allow for treatment up to the visit window. All but twenty patients had an endoscopic evaluation after 4 weeks of treatment. Following the endoscopic evaluation, all patients received subsequent 4 weeks of open-label treatment with lansoprazole 30 mg QD. Repeated symptom evaluation to detect symptom pattern was assessed during this period.
  • the study design is shown in Figure 4.
  • linaprazan glurate 25 mg, 50 mg, 75 mg, 100 mg, and dummies
  • the tablet formulation as shown in table 1 was used.
  • the active comparator lansoprazole 30 mg and its dummy were administered as capsules once daily in the morning.
  • the study drugs were taken with 100 mL of noncarbonated water at least 30 minutes prior to meals. The duration of double-blind treatment was 28 days -2/+5 days.
  • each patient received 2 tablets (containing doses of linaprazan glurate (LG) or its dummy) and one capsule (containing lansoprazole or its dummy) in the morning and 2 tablets (containing doses of linaprazan glurate (LG) or its dummy) in the evening, according to the scheme below:
  • the study comprised 6 visits at the site and 3 telephone visits. Based on the endoscopy findings and/or signed informed consent form (ICF), the screening visit (Visit 1) took place not more than 7 working days prior to randomization and the first dose administration (Visit 2). All patients then visited the study clinic/investigational site after 7 (Visit 3), 14 (Visit 4) and 28 days (Visit 5) and at the End of Study/Early Termination visit (Visit 9). There were 3 weekly telephone visits after Visit 5.
  • ICF informed consent form
  • Gastroesophageal reflux disease with endoscopically confirmed erosive esophagitis o LA grade C or D ⁇ 7 working days before randomization (with or without historical PPI treatment) or o LA grade A or B ⁇ 7 working days before randomization and
  • Any of the following screening laboratory test are exclusionary: o Serum ALT or AST > 1.5 x the upper limit of normal (ULN) for the central laboratory conducting the test; o Serum Total Bilirubin > 1.5 x ULN for the central laboratory conducting the test; o Serum Creatinine > 1.5 x ULN for the central laboratory conducting the test; o Estimated glomerular filtration rate ⁇ 59 mL/min (calculated using the Modification of Diet in Renal Disease equation).
  • HCV human immunodeficiency virus
  • HBsAg Hepatitis B surface antigen
  • anti-HBcAg antibody to Hepatitis B core antigen
  • a nti- HCV antibody to Hepatitis C virus
  • the primary objective of the study was to support dose selection for linaprazan glurate, through assessment of healing of erosive esophagitis due to GERD after 4 weeks of treatment. Healing of erosive esophagitis due to GERD was based on endoscopic assessment after 4 weeks of double-blind treatment.
  • a secondary objective of the study was the safety and tolerability of the four dose levels of linaprazan glurate and lansoprazole, with lansoprazole serving as the active comparator.
  • Another secondary objective of the study was the reflux related symptom pattern during the initial 4 weeks treatment with four dose levels of linaprazan glurate and with lansoprazole, and the symptom pattern during the subsequent additional 4 weeks (weeks 5-8) open-label treatment with lansoprazole 30 mg QD.
  • Heartburn-free 24-hour days and 24-hour days with at most mild heartburn symptoms were assessed based on modified eDiary (mRESQ-eD), including splits into day- and nighttime evaluations.
  • the response in the linaprazan glurate 100 mg dose group was lower than expected, but this group comprised a higher proportion of the most severe (“hard to treat") LA grade D patients than the other dose groups.
  • the 4-week LA grade was A, i.e., these patients failed on the finish line.
  • Reflux related symptoms were assessed based on a modified RESQ-eDiary (mRESQ-eD). Patients were asked to report every 12-hours, once before the morning dose and once before the evening dose of the Investigational Medicinal Product (IMP). Results for erosive patients of all LA grades are shown in Table 4.
  • Double-blind period (week 1 to 4)
  • FIG. 10 A chart of the mRESQ-eD assessed heartburn-free 24-hour days over a week for all LA grade A/B/C/D patients is shown in Figure 10, and the corresponding chart for LA grade C/D patients is shown in Figure 11.
  • Double-blind period (week 1 to 4)
  • the highest percentage of heartburn-free days were by treatment group LG 50 mg at week 1 and 4, by LG 75 mg at week 2 and by LG 100 mg at week 3.
  • the lansoprazole group reported the lowest percentage of heartburn-free days week 2-4.
  • All linaprazan glurate treatment groups reported more heartburn-free days week 5 to week 8 compared to the lansoprazole treatment group.
  • the LG 75 mg treatment group reported the highest percentage of heartburn-free days (72.6% and 73.0%, respectively), while at week 7 and week 8 the highest percentage of heartburn-free days was reported for the LG 25 mg treatment group (81.9% and 87.6%, respectively).
  • LA Grade A/B the highest percentage of heartburn-free days was reported by treatment group LG 75 mg at week 5, lansoprazole reported the highest at week 6 and treatment group LG 25 mg reported the highest percentage of heartburn-free days at weeks 7 and 8.

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Abstract

L'invention concerne le linaprazan glurate, ou un sel pharmaceutiquement acceptable de celui-ci, destiné à être utilisé dans le traitement ou la prévention d'une maladie inflammatoire gastro-intestinale ou d'une maladie liée à l'acide gastrique, telle qu'une maladie du reflux gastro-œsophagien (érosif). Le traitement implique l'administration orale de linaprazan glucosane, ou d'un sel pharmaceutiquement acceptable de celui-ci, à un patient en une quantité d'environ (25) à environ (100) mg une fois ou deux fois par jour.
PCT/EP2023/080637 2023-05-08 2023-11-03 Linaprazan glurate pour le traitement du reflux gastro-œsophagien pathologique (gerd) Pending WO2024230943A1 (fr)

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MX2025013362A MX2025013362A (es) 2023-05-08 2025-11-07 Tratamiento de la enfermedad por reflujo gastroesofagico (erge)

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