Principal Investigator: Kathryn Peterson
Keywords: Eosinophilic Gastritis , Eosinophilic Gastroenteritis , EG , EGE Department: Gastroenterology
IRB Number: 00130071
Specialty: Gastroenterology, Gastroenterology
Sub Specialties: Endoscopy
Recruitment Status: Recruiting

Contact Information

Amy Holman

Brief Summary

Based on experience with AK002 in healthy volunteers and in patients with ISM, CU, severe AC, and EG/EoD, the proposed AK002 dose regimen of 6 total doses is 1 mg/kg for the first infusion, followed by 5 doses of 3 mg/kg, administered every 4 weeks.

This dosing regimen is supported by the safety experience in 51 healthy volunteers, 25 patients with ISM, 5147 patients with CU, 30 patients with severe AC, 8 patients with mast cell gastritis, and 65 patients with EG/EoD. To date, a range of AK002 doses from 0.0003 mg/kg to 10 mg/kg have been tested, and the maximum tolerated dose (MTD) has not been reached.

In the double-blind, placebo -controlled Phase 2 study in patients with EG and/or EoD (previously referred to as EGE), 2 dose levels were evaluated: a lower dose regimen (4 monthly doses of AK002 at 0.3, 1, 1 and 1 mg/kg) and a higher dose regimen (4 monthly doses of 0.3, 1, 3 and 3 mg/kg). Both regimens produced dramatic reduction in tissue eosinophils and were associated with substantial improvement in symptoms. However, numerically greater improvements were observed in the high dose arm compared with the low dose arm.

As there were no differences in safety or tolerability between the 2, dosing regimens and the higher regimen appeared to be more effective, the 3 mg/kg dose was selected for this confirmatory Phase 3 study. 

Additionally, a starting dose of 1 mg/kg was well tolerated in patients with EG and/or EoD in the long-term extension study that followed the Phase 2 study, supporting the use of 1 mg/kg as the starting dose in this study.

The infusions were generally well tolerated at all doses with most IRR being mild to moderate, and very few adverse events outside the infusion window. Patients with ISM, CU, severe AC, mast cell gastritis, and EG/EoD have received monthly doses of 1 mg/kg and 3 mg/kg AK002. Subsequent infusions in multiple dose cohorts were associated with fewer IRR when compared with the first infusion.

Therefore, the proposed dosing regimen is a starting dose of 1 mg/kg, with a second dose of 3 mg/kg, followed by 4 doses of 3 mg/kg for subsequent infusions, this Phase 3 study with AK002 in patients with EG and/or EoD.

Study Objectives

Primary Objective

The primary objective of the study is to evaluate the efficacy and safety of AK002 in patients with moderately to severely active EG and/or EoD, with inadequate or loss of response to, or intolerance to standard therapies, when compared with placebo. Efficacy will be measured by co-primary endpoints, namely:

  • First co-primary endpoint: Proportion of Responders: A responder is a patient achieving the following peak eosinophil counts.

  • Eosinophilic gastritis (EG): Mean eosinophil count ≤4 cells/5 gastric or hpf.

  • Eosinophilic duodenitis (EoD): Mean eosinophil count ≤15 cells/3 duodenal hpf.

  • EG and EoD: Mean eosinophil count ≤4 cells/5 gastric hpf and mean eosinophil count ≤15 cells/3 duodenal hpf.

  • Second co-primary endpoint: Mean absolute change in (TSS) from baseline to Weeks 22-24 as measured by the (PRO) questionnaire.

Secondary Objectives

The secondary objectives of the study are to further characterize the efficacy of AK002 as measured by:

  • Percent change in tissue eosinophils from Baseline to Week 24.

  • Proportion of patients achieving peak gastric and/or duodenal intraepithelial eosinophil count of ≤1 eosinophils/hpf at Week 24.

  • Number of treatment responders as defined by >30% improvement in TSS and mean eosinophil count ≤4 cells per hpf in 5 gastric hpf and/or mean eosinophil count ≤15 cells per hpf in 3 duodenal hpf.

  • Proportion of patients who show > or equal to 50% reduction in TSS from Baseline to Weeks 22-24.

  • Proportion of patients who show > or equal to 70% reduction in TSS from Baseline to Weeks 22-24.

  • Percent change in weekly TSS over time.

4.3 Exploratory Objectives

The exploratory objectives are to evaluate the effect of AK002 by comparing AK002 to placebo treatment for the following parameters:

  • Change in mast cell counts

  • Change in SF-36

  • For patients with concomitant EoE:
    – Proportion of patients achieving peak esophageal intraepithelial count of ≤6 eosinophils/hpf at Week 24.

  • Change in peripheral blood eosinophils.

Safety Objectives

To evaluate the safety and tolerability of AK002 by determining incidence and severity of adverse events, study withdrawals due to adverse events, changes in vital signs and laboratory tests including immunogenicity, changes in concomitant medication use due to adverse events, and other safety parameters.

Inclusion Criteria

  1. Provide written informed consent.

  2. Male or female aged ≥18 and ≤80 years at the time of signing the informed consent for entry.

  3. Baseline endoscopic biopsy with >30 eosinophils/hpf in 5 hpf in the stomach and/or >30 eosinophils/hpf in 3 hpf in the duodenum, as determined by central histology assessment of biopsies collected during the screening EGD. Prior EGD may be used for eligibility as long as the EGD occurred within 3 months of the first screening visit for the AK002-016 study and were performed and centrally assessed as for the AK002-016 study.

  4. Completion of at least 4 daily PRO questionnaires per week for a minimum of 3 weeks during screening.

  5. A weekly average score of abdominal pain, nausea, and/or diarrhea ≥3 on the PRO questionnaire (score from 0–10) and a weekly average TSS of ≥10 for at least 2 weeks of screening.

  6. Patients with inadequate or loss of response to, or who were intolerant to standard therapies for EG/EoD symptoms which could include PPI, antihistamines, systemic or topical corticosteroids, and/or diet, among others.

  7. If patient is on pre-existing dietary restrictions, willingness to maintain dietary restrictions throughout the study.

  8. Willing and able to comply with all study procedures and visit schedule, including follow-up visits.

  9. Female patients must be either post-menopausal for at least 1 year with FSH level
    >30 mIU/mL at screening or surgically sterile (tubal ligation, hysterectomy or bilateral oophorectomy) for at least 3 months, or if of childbearing potential, have a negative pregnancy test and agree to use dual methods of contraception, or abstain from sexual activity from screening until the end of the study, or for 120 days following the last dose of study drug, whichever is longer

    Male patients with female partners of childbearing potential must agree to use a highly effective method of contraception from screening until the end of the study or for 120 days following the last dose of study drug, whichever is longer. All fertile men with female partners of childbearing potential should be instructed to contact the Investigator immediately if they suspect their partner might be pregnant (e.g., missed or late menstrual period) at any time during study participation

Exclusion Criteria

  1. Use of systemic or topical corticosteroids exceeding the equivalent of 10 mg/day of prednisone within 4 weeks prior to the screening visit.

  2. Change in the dose of corticosteroids (systemic or topical), PPI, leukotrienes, or diet therapy within 4 weeks prior to screening.

  3. Treatment with any immunosuppressive or immunomodulatory drugs that may interfere with the study within 12 weeks prior to the screening visit.

  4. Prior exposure to AK002 or known hypersensitivity to any constituent of the study drug.

  5. Active Helicobacter pylori infection, unless treated and confirmed to be negative prior to randomization and histology per repeat EGD and symptoms still qualify for enrollment after treatment. 

  6. Confirmed history of inflammatory bowel disease, celiac disease, achalasia or esophageal surgery.

  7. History of bleeding disorders and/or esophageal varices considered to be clinically significant by the Investigator. 

  8. Other significant causes of gastric and/or duodenal eosinophilia or eosinophilic granulomatosis with polyangiitis (EGPA).

  9. Confirmed diagnosis of Hypereosinophilic Syndrome (HES).

  10. Women who are pregnant, breastfeeding, or planning to become pregnant while participating in the study.

  11. Presence of an abnormal laboratory value considered to be clinically significant by the Investigator.

  12. Any disease, condition (medical or surgical), or cardiac abnormality, which, in the opinion of the Investigator, would place the patient at increased risk.

  13. History of malignancy, except carcinoma in situ, early stage prostate cancer, or non-melanoma skin cancers. However, cancers that have been in remission for more than 5 years and are considered cured, can be enrolled (with the exception of breast cancer).

  14. Treatment for a clinically-significant helminthic parasitic infection within 6 months of screening.

  15. Positive helminthic infection on Ova and Parasite (O&P) test.

  16. Seropositive for Strongyloides stercoralis at screening, except for patients with past but resolved disease.

  17. Seropositive for HIV or hepatitis results, except for vaccinated patients or patients with past but resolved disease.

  18. Vaccination with live attenuated vaccines within 30 days prior to initiation of treatment in the study, during the treatment period, or vaccination expected within 5 half-lives (4 months) of study drug administration. All types and formulations of vaccines (including live attenuated vaccines) authorized by FDA or other regulatory authority for the prevention of COVID-19 may be administered before, during, or after this study. The vaccine should not be administered within 7 days prior to and within 7 days after the administration of AK002 so that any side effects caused by either of the 2 medications can be more easily determined

  19. Participation in a concurrent interventional study with the last intervention occurring within 30 days prior to study drug administration or 90 days or 5 half-lives, whichever is longer, for biologic products.

  20. Known history of alcohol, drug, or other substance abuse or dependence considered by the Investigator to be ongoing and clinically significant.

  21. Any other reason that in the opinion of the Investigator or the Medical Monitor makes the patient unsuitable for enrollment.