Safety and Efficacy of Oral Administration of the Phage Cocktail, VRELysin™, In Healthy and VRE-Colonized Subjects

PHASE 1 INCLUSION CRITERIA: To be eligible to participate in the Phase 1 segment of the study, each subject mustfulfill ALL of the following criteria:

1. Age 18 to 50 years old.
2. Body mass index (BMI) of ≥19 kg/m2 to ≤40 kg/m2.
3. Has the ability to understand the study procedures and risks involved with the study,voluntarily agrees to participate by giving written informed consent and is willing toadhere to dose and visit schedules. The subject must be able to read, understand, andcomplete questionnaires and memory aids.
4. Agrees not to enroll in another study of an investigational research agent during thestudy, with the exception of potentially lifesaving or coronavirus disease of 2019 (COVID-19)-related experimental treatments.
5. Good general health as shown by medical history, physical examination, and screeninglaboratory tests or clinical laboratory abnormalities per clinical judgment ofPrincipal Investigator (PI).
6. Agrees not to donate blood or blood products during participation in the study or for 30 days after completion of study participation.
7. Has negative serology results for HIV, hepatitis B surface antigen (HBsAg), andhepatitis C virus (HCV) antibody.
8. Female subjects must have a negative serum or urine beta human chorionic gonadotropin (β-HCG) pregnancy test at Screening and within 24 hours of initial treatment on Day 1. a. Persons who are NOT of reproductive potential due to having undergone totalhysterectomy or bilateral oophorectomy (verified by medical records) are not requiredto undergo pregnancy testing.
9. Female subjects of reproductive potential must agree to use adequate contraception,defined as consistent and correct use of an FDA-recommended contraceptive method orcombination of methods in accordance with the product label. For example:
10. Barrier method (such as condoms, diaphragm, or cervical cap) used in conjunctionwith spermicide and another method, such as prescription hormonal contraceptive;
11. Intrauterine device (IUD);
12. Prescription hormonal contraceptive taken or administered via oral (pill),transdermal (patch) subdermal, or intramuscular route used in combination withanother method, such as barrier methods;
13. Total abstinence;
14. Sterilization of a monogamous female participant's male partner prior to entryinto the study. Note: periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulationmethods) and withdrawal are not acceptable methods of contraception.
15. Female subjects must also agree not to seek pregnancy through alternative methods,such as artificial insemination or in vitro fertilization until after the lastrequired study visit is completed.
16. Male subjects must agree to use adequate contraception, defined as consistent andcorrect use of an FDA-recommended contraceptive method in accordance with the productlabel (see above), for the duration of the study and refrain from donating spermduring this period.

PHASE 1 EXCLUSION CRITERIA: To be eligible to participate in Phase 1, subjects must NOT fulfill ANY of the followingcriteria:

1. Investigational research agents received within 30 days before first treatment.
2. Pregnant or breastfeeding.
3. Regular (no more than once a week) use of antidiarrheals, stool softeners, laxatives,antacids, or other agents to lower stomach acidity.
4. Use of oral or intravenous antimicrobials within 2 weeks of study start or planned useduring active study phase. Topical treatments are allowed.
5. Proton pump inhibitors, H2 blockers or antacids within 48 hours prior to dosing orplanned use during active study phase.
6. Abnormal bowel patterns, defined by <3 stools per week or >2 stools per day on averageover the past 6 months.
7. History of diarrhea in the 7 days prior to treatment. Outpatient diarrhea is definedas ≥ 3 unformed (Grade 3 or greater) loose stools in 24 hours.
8. Use of oral supplemental probiotics in the form of pills or tablets within 2 weeks ofstudy start or planned use during active study phase.
9. History of myocarditis, pericarditis, cardiomyopathy, congestive heart failure withpermanent sequelae, clinically significant arrhythmia (including any arrhythmiarequiring medication, treatment, or clinical follow-up).
10. Clinically significant medical condition, physical examination findings, clinicallysignificant abnormal laboratory results, or past medical history with clinicallysignificant implications for current health. A clinically significant condition orprocess includes, but is not limited to:
11. Any contraindication to repeated blood draws;
12. A condition or process for which signs or symptoms could be confused withreactions to treatment;
13. Any of the following in the past 10 years: Crohn's disease, ulcerative colitis,irritable bowel disease, celiac disease, stomach, or intestinal ulcers, or 2 ormore episodes of inflammatory arthritis (joint pain and swelling);
14. Bacterial infection at time of enrollment;
15. Blood in stool on >2 occasions (other than small amounts from straining) in past 12 months;
16. Recurrent diarrhea (>5 episodes in past 6 months, each lasting >3 days or more).
17. History of excessive alcohol consumption or drug dependence within last 3 years.
18. Any medical, psychiatric, occupational, or other condition that, in the judgment ofthe investigator, would interfere with, or serve as a contraindication to, protocoladherence, assessment of safety, or a subject's ability to give informed consent.
19. Psychiatric condition that precludes compliance with the protocol. Specificallyexcluded are persons with psychoses within the past 3 years, ongoing risk for suicide,or history of suicide attempt or gesture within the past 3 years.
20. Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, orplatelet disorder requiring special precautions).
21. Malignancy (Not excluded from participation: subject who has had malignancy excisedsurgically and who, in the investigator's estimation, has a reasonable assurance ofsustained cure, or who is unlikely to experience recurrence of malignancy during theperiod of the study).
22. Seizure disorder/epilepsy: History of seizure(s) within past 3 years. Also exclude ifsubject has used medications in order to prevent or treat seizure(s) at any timewithin the past 3 years.
23. Asplenia: any condition resulting in the absence of a functional spleen.
24. History of chronic gastrointestinal illness, including severe dyspepsia, lactoseintolerance, or other significant gastrointestinal tract disease (e.g., irritablebowel syndrome/disease, inflammatory bowel syndrome, gastric ulcer disease, Crohn'sdisease).
25. Any other criteria which, in the Investigator's opinion, would compromise the abilityof the subject to participate in the study, the safety of the study, or the results ofthe study.
26. Known allergy or hypersensitivity to an excipient in the study drug or placebo. PHASE 2A INCLUSION CRITERIA: To be eligible to participate in the Phase 2a segment of the study, each subject mustfulfill ALL of the following criteria:
27. Age 18 to 50 years old.
28. BMI of ≥19 kg/m2 to ≤40 kg/m2.
29. Has the ability to understand the study procedures and risks involved with the study,voluntarily agrees to participate by giving written informed consent and is willing toadhere to dose and visit schedules. The subject must be able to read, understand, andcomplete questionnaires and memory aids.
30. Agrees not to enroll in another study of an investigational research agent during thestudy, with the exception of potentially lifesaving or COVID-19-related experimentaltreatments.
31. Agrees not to donate blood or blood products during participation in the study or for 30 days after completion of study participation.
32. Has negative serology results for HIV, HBsAg, and HCV antibody.
33. Has 2 consecutive positive VRE stool cultures (at least 7 days apart) that aresusceptible to VRELysin. The second stool culture must be within 7 days ofrandomization.
34. Able to tolerate and take oral medication at time of randomization.
35. Female subjects must have a negative serum or urine β-HCG pregnancy test at Screeningand within 24 hours of initial treatment on Day 1.
36. Persons who are NOT of reproductive potential due to having undergone totalhysterectomy or bilateral oophorectomy (verified by medical records) are not requiredto undergo pregnancy testing.
37. Female subjects of reproductive potential must agree to use adequatecontraception, defined as consistent and correct use of an FDA-recommendedcontraceptive method or combination of methods in accordance with the productlabel. For example:
38. Barrier method (such as condoms, diaphragm, or cervical cap) used in conjunctionwith spermicide and another method, such as prescription hormonal contraceptive;
39. IUD;
40. Prescription hormonal contraceptive taken or administered via oral (pill),transdermal (patch) subdermal, or intramuscular route used in combination withanother method, such as barrier methods;
41. Total abstinence;
42. Sterilization of a monogamous female participant's male partner prior to entryinto the study. Note: periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulationmethods) and withdrawal are not acceptable methods of contraception.
43. Female subjects must also agree not to seek pregnancy through alternative methods,such as artificial insemination or in vitro fertilization until after the lastrequired study visit is completed.
44. Male subjects must agree to use adequate contraception, defined as consistent andcorrect use of an FDA-recommended contraceptive method in accordance with the productlabel (see above), for the duration of the study and refrain from donating spermduring this period. PHASE 2A EXCLUSION CRITERIA: To be eligible to participate in Phase 2a, subjects must NOT fulfill ANY of the followingcriteria:
45. Investigational research agents received within 30 days before first treatment.
46. Pregnant or breastfeeding.
47. Regular (no more than once a week) use of antidiarrheals, stool softeners, laxatives,antacids, or other agents to lower stomach acidity.
48. Use of oral or intravenous antimicrobials within 2 weeks of study start or planned useduring active study phase. Topical treatments are allowed.
49. Proton pump inhibitors, H2 blockers or antacids within 48 hours prior to dosing orplanned use during active study phase.
50. Abnormal bowel patterns, defined by <3 stools per week or >2 stools per day on averageover the past 6 months.
51. History of diarrhea in the 7 days prior to treatment. Outpatient diarrhea is definedas ≥3 unformed (Grade 3 or greater) loose stools in 24 hours.
52. Taking supplemental probiotics in the form of pills or tablets within 2 weeks.
53. History of myocarditis, pericarditis, cardiomyopathy, congestive heart failure withpermanent sequelae, clinically significant arrhythmia (including any arrhythmiarequiring medication, treatment, or clinical follow-up).
54. Clinically significant medical condition, physical examination findings, clinicallysignificant abnormal laboratory results, or past medical history with clinicallysignificant implications for current health. A clinically significant condition orprocess includes but is not limited to:
55. Any contraindication to repeated blood draws;
56. A condition or process for which signs or symptoms could be confused withreactions to treatment;
57. Any of the following in the past 10 years: Crohn's disease, ulcerative colitis,irritable bowel disease, celiac disease, stomach, or intestinal ulcers;
58. Blood in stool on >2 occasions (other than small amounts from straining) in past 12 months;
59. Recurrent diarrhea (>5 episodes in past 6 months, each lasting >3 days or more);
60. Requires hemodialysis.
61. History of excessive alcohol consumption or drug dependence within last 3 years.
62. Any medical, psychiatric, occupational, or other condition that, in the judgment ofthe investigator, would interfere with, or serve as a contraindication to, protocoladherence, assessment of safety, or a subject's ability to give informed consent.
63. Psychiatric condition that precludes compliance with the protocol. Specificallyexcluded are persons with psychoses within the past 3 years, ongoing risk for suicide,or history of suicide attempt or gesture within the past 3 years.
64. Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, orplatelet disorder requiring special precautions).
65. Malignancy (Not excluded from participation: subject who has had malignancy excisedsurgically and who, in the investigator's estimation, has a reasonable assurance ofsustained cure, or who is unlikely to experience recurrence of malignancy during theperiod of the study).
66. Seizure disorder/epilepsy: History of seizure(s) within past 3 years. Also exclude ifsubject has used medications in order to prevent or treat seizure(s) at any timewithin the past 3 years.
67. Asplenia: any condition resulting in the absence of a functional spleen.
68. History of chronic gastrointestinal illness, including severe dyspepsia, lactoseintolerance, or other significant gastrointestinal tract disease (e.g., irritablebowel syndrome, inflammatory bowel syndrome, gastric ulcer disease).
69. Known allergy or hypersensitivity to an excipient in the study drug or placebo.
70. Patients with active infection, a systemic infection requiring treatment, or any otherunstable medical condition that could interfere with the study objectives.
71. Any other criteria which, in the Investigator's opinion, would compromise the abilityof the subject to participate in the study, the safety of the study, or the results ofthe study.