Principal Investigator: Kathryn Peterson
Keywords: Eosinophilic Duodenitis , EoE , AK002 , EoD , Eosinophilic Department: Gastroenterology
IRB Number: 00143100
Specialty: Gastroenterology, Gastroenterology, Gastroenterology
Sub Specialties: Esophageal Diseases, Endoscopy
Recruitment Status: Not yet recruiting

Contact Information

Amy Holman
amy.holman@hsc.utah.edu
8015859155

Brief Summary

Eosinophilic Gastrointestinal Disorders Eosinophilic gastrointestinal disorders (EGID) are chronic inflammatory disorders characterized by infiltration of eosinophils along different segments of the gastrointestinal tract, in the absence of any other cause of the eosinophilia (Caldwell, 2014).

EG and/or EoD are traditionally believed to be rare types of EGID that are characterized by chronic, often severe inflammation due to patchy or diffuse infiltration of eosinophils into layers of the stomach, small intestine, or both the stomach and small intestine (Prussin, 2014; Reed, 2015; Zhang, 2017). The diagnosis is based on clinical presentation (gastrointestinal symptoms) combined with increased tissue eosinophils in biopsy specimens from the stomach and/or duodenum without any other cause for the eosinophilia. Involvement of the small intestine is typically assessed by performing duodenal biopsies using an esophago-gastro-duodenoscopy (EGD) and has been referred to as eosinophilic gastroenteritis or eosinophilic enteritis, though EoD is more appropriate. The gastrointestinal symptoms are believed to be due to the release of inflammatory mediators from activated eosinophils, and also likely mast cells. Symptoms that are often severe and debilitating commonly include abdominal pain, nausea, bloating, early satiety (fullness before finishing a meal), abdominal cramping, vomiting, diarrhea, and weight loss (Alhmoud, 2016; Lopez-Medina, 2015; Mansoor, 2017; Reed, 2015). Jensen et al. (2016) estimated the prevalence of EG and EoD to be 6.3/100,000 and 8.4/100,000 respectively (for patients ages 1–64 years old). Mansoor et al. (2017) estimated the overall prevalence of EG to be 5.1/100,000 persons, though emerging evidence suggests that true prevalence is higher (Licari, 2020). Patients may also have concomitant atopic diseases like food allergy, asthma, and atopic dermatitis, which further impact qualify of life and contribute to health care costs. Additionally, 8% to 10% of patients have concomitant EoE (Jensen, 2016). There are no FDA-approved treatments for EG and/or EoD. Current therapies and disease management include dietary restriction/elimination, PPI, antihistamines, systemic or topical corticosteroids, and occasional off-label use of immunomodulatory biologics (Prussin, 2014; Reed, 2015; Zhang, 2017). Proton pump inhibitors have little to no benefit in patients with EG and/or EoD, despite reports of providing partial benefit in some patients with EoE (Katz, 2013). Restricted/elemental diets are not effective long-term treatment as they require strict compliance and, in the case of elemental diets, are expensive and are often not reimbursed by insurance. In addition, compliance is poor, and patient quality of life is greatly impacted (Bedell, 2018; Peterson, 2013; Wechsler, 2014). Corticosteroids, systemic or topical (swallowed), have been shown to provide symptom relief but are not appropriate for long-term treatment due to numerous side effects and associated risks including adrenal insufficiency, bone demineralization, increased chance of infection, osteoporosis, behavioral issues, and weight gain. By markedly reducing the number of blood and tissue eosinophils and inhibiting the activation of mast cells, AK002 may be useful in the treatment of patients with EG and/or EoD. This premise is supported by the Phase 2 data with AK002 that shows significant improvement in histology and symptom severity in these patients. Given there are no approved therapies for these chronic and debilitating diseases, better treatment options are clearly needed to manage EG and EoD.

Primary Objective: To evaluate the efficacy and safety of 6 doses of AK002 in patients with moderate to severe EoD when compared with placebo. Efficacy will be evaluated by the following co-primary endpoints: 1) Proportion of Responders, where a responder is a patient achieving a mean peak duodenal eosinophil count ≤15 cells/3 duodenal hpf. 2) Mean absolute change in TSS from baseline to Weeks 22–24 as measured by the PRO questionnaire. Safety will be evaluated by AE reporting, laboratory safety tests, changes in vital signs, changes in concomitant medication use due to AE, immunogenicity, and other safety parameters.

Secondary Objectives: To further characterize the efficacy of AK002 in patients with EoD as measured by: • Percent change in tissue eosinophils from baseline to Week 24. • Proportion of patients achieving peak duodenal intraepithelial eosinophil count of ≤1 eosinophil/hpf at Week 24. • Number of treatment responders as defined by >30% improvement in symptoms and mean eosinophil count ≤15 cells/hpf in 3 duodenal hpf. • Proportion of patients who show ≥50% reduction in TSS from baseline to Weeks 22–24. • Proportion of patients who show ≥70% reduction in TSS from baseline to Weeks 22–24. • Percent change in weekly TSS over time.

Exploratory Objectives To evaluate the effect of AK002 by comparing AK002 to placebo treatment for the following parameters: • Change in peripheral blood eosinophils. • Changes in eosinophil counts from baseline compared to post-treatment in the terminal ileum, colon, and rectum will be noted. • For patients with concomitant EoE: Proportion of patients achieving peak esophageal intraepithelial count of ≤6 eosinophils/hpf at Week 24. • Change in mast cell counts. • Change in SF-36.

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

OLE Objective The objective of the OLE period is to evaluate long-term safety and tolerability of up to 6 doses of open-label AK002 in subjects with active EoD only. The Medical Monitor will review OLE period data relating to safety and tolerability throughout the course of OLE dosing.

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 3 hpf in the duodenum, as determined by central histology assessment of biopsies collected during the screening EGD + colonoscopy, without any other significant cause for the eosinophilia.

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

6) Inadequate or loss of response to, or intolerant to standard therapies for 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 later menstrual period) at any time during study participation.

Exclusion Criteria

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

2) Baseline endoscopic biopsy with ≥30 eosinophils/hpf in 5 hpf in the gastric mucosa as determined by central histology assessment of biopsies collected during the screening EGD.

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

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

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

6) Active Helicobacter pylori infection as confirmed by stool antigen test for H.pylori.

7) History of inflammatory bowel disease, other chronic inflammatory diseases in the colon (with the exception of eosinophilic colitis), celiac disease, achalasia, or esophageal surgery.

8) History of bleeding disorders and/or esophageal varices.

9) Other causes of duodenal eosinophilia or eosinophilic granulomatosis with polyangiitis.

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 nonmelanoma skin cancers. However, patients with cancers that have been in remission for more than 5 years and are considered cured can be enrolled.

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.

17) Seropositive for HIV or hepatitis at screening, except for vaccinated patients or patients with past but resolved hepatitis, at screening. See Appendix 12.

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. This exclusion criterion does not apply to all types and formulations of vaccines (including live attenuated vaccines) authorized by FDA or other regulatory authority for the prevention of COVID-19, which may be administered before, during, or after the study.

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 that is 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.